Orally disintegrable tablets

ABSTRACT

An orally disintegrable tablet, of the present invention, which comprises (i) fine granules having an average particle diameter of 400 μm or less, which fine granules comprise a composition coated by an enteric coating layer, said composition having 10 weight % or more of an acid-labile physiologically active substance and (ii) an additive, has superior disintegrability or dissolution in the oral cavity so that it can be used for treatment or prevention of various diseases, as an orally disintegrable tablet capable of being administered to the aged or children and easily administered without water. Also, because the tablet of the present invention contains fine granules having the average particle diameter such that it will not impart roughness in mouth, it can be administered easily without discomfort at the administration.

TECHNICAL FIELD

[0001] The present invention relates to an orally disintegrable tablethaving a characteristic of fast disintegration in the oral cavity evenwithout water.

BACKGROUND ART

[0002] Pharmaceutical solid preparations, for example, tablets, usuallyare prepared to make pharmaceutically active ingredients absorb in adigestive organ by disintegration or dissolution through oraladministration, without fast disintegration or dissolution in the oralcavity.

[0003] JP-A-6-502194 (U.S. Pat. No. 5,464,632) discloses a rapidlydisintegrable multiparticulate tablet, the excipient mixture of which issuitable for imparting a disintegration rate such that the tabletdisintegrates in the mouth in less than sixty seconds, characterized bythe fact that the active substance is present in the form of coatedmicrocrystals or coated or uncoated microgranules. However, there is nodisclosure of an acid-labile physiologically active substance with abasic inorganic salt as the active substance, weight percentage of theactive substance in the excipient mixture, or the size of the coatedmicrogranule.

[0004] On the other hand, JP-A-5-92918 discloses a powder consisting ofa fine-particle core coated with a water-soluble high molecular compoundand at least one physiologically active substance, and having a granulesize of practically up to 500 μm. However, there is no disclosure of anacid-labile physiologically active substance with a basic inorganic saltas the physiologically active substance, weight percentage of the activesubstance in the coated granule or the size of the coated granule.

[0005] Jp-A-63-301816 and U.S. Pat. No. 5,026,560 disclose sphericalgranules having a core coated with spraying powder containing a drug andlow substituted hydroxypropylcellulose. However, there is no disclosureof orally disintegrable tablet.

[0006] EP-A-0452862 discloses a spherical granule obtained by coating apharmacologically inactive spherical seed core having at least 50 weight% microcrystalline cellulose and an average particle size of 100-1000μm, with a powder comprising an active ingredient, by using an aqueousbinding solution, and spraying an aqueous solution or suspension of acoating agent thereon. However, most of the particle sizes of thusobtained granules are 500 μm or more.

[0007] JP-A-1-268627, JP-A-1-268628 and JP-A-8-27033 disclosepharmaceutical compositions using erythritol, respectively. However,there is no disclosure of solid pharmaceutical composition characterizedfast disintegration in the oral cavity.

[0008] JP-A-9-48726 discloses a buccal formulation consisting of a drugand a substance wetting in a mouldable way on humidifying, and retaininga shape after moulding and drying. As such substance, sugars, sugaralcohols and water-soluble polymers are exemplified.

[0009] JP-A-5-271054 discloses production of fast dissolving tabletscomprising an active ingredient and sugars.

[0010] JP-A-9-71523 discloses a tablet with rapid disintegration in theoral cavity comprising medicine, crystalline cellulose, low-substitutedhydroxypropyl cellulose and lubricant.

[0011] However, these prior art references nowhere disclose anacid-labile physiologically active substance with a basic inorganic saltas an active substance, weight percentage of the active substance in thetablet or the size of the coated fine granule.

[0012] To accompany an aging population and their changes in lifeenvironment, it is desired to develop an orally disintegrable solidpreparation capable of being administered without water, retaining theconvenience for use which is a characteristic of a tablet, and beingadministered on demand easily, anytime and anywhere, without water.

[0013] Conventional granules have large particle diameters, whichresults in inferior workability when dispensing, and also results indifficulties in consistently adding a regular amount of the granuleswhen they are combined into tablets or capsules. Granules having a largeparticle diameter (400 μm or more of average particle diameter) alsoproduce a feeling of roughness in the mouth. Accordingly, especiallywhen used in an orally disintegrable tablet, the average particlediameter of the included granules must be about 400 μm or less,preferably about 350 μm.

[0014] For many reasons, such as, masking a bitter taste, or providingenteric abilities or release abilities, it is desirable to prepare thesolid pharmaceutical preparations as granules (or fine granules). Inparticular, in case of granules or fine granules in which the activeingredient of the drug is enteric coated to impart enteric dissolution,there is a need for enteric coating to prevent dissolution by stomachacid (i.e., to make the preparation acid-resistance). It is necessary tocoat the whole surface of the particle -before the enteric coating-(including a case of the crystal of physiologically active substanceonly, and a case of the granule produced by granulation), with theenteric coating. Namely, at least some uniform thickness (at least 20 μmor more) of the coating layer is needed. Even a portion of thin and weakcoating, is undesirable because acid-resistance is lowered. Accordingly,before the enteric coating, it is necessary that the particle is asspherical with smooth surface as possible in form, as uniform aspossible in size, and has less cavity.

[0015] It is very difficult to produce an enteric coated fine granulewith an average particle diameter of 400 μm or less, when the coating isperformed so that at least 20 μm thickness of coating layer may coat thewhole particle, and the enteric coated particle contains a basicinorganic salt for stabilization of an acid-labile physiologicallyactive substance, and where it contains binders for maintaining thestrength of the particle and/or disintegrants for maintaining thedisintegrability (dissolution) of the particles. Further, in the casewhere the content of the acid-labile physiologically active substance isincreased, it is necessary to also increase the content of theexcipients such as basic inorganic salt, binders and disintegrants.Furthermore, it is very difficult to produce a small enteric coated finegranule containing the physiologically active substance in high content.

[0016] Accordingly, it is desired to develop a fine granule which iscoated with the enteric coating layer on the composition containing thephysiologically active substance such as a physiologically activesubstance containing a basic inorganic salt and which has a particlediameter so that roughness or oral discomfort is not felt, to develop afine granule containing the physiologically active substance, i.e., theactive ingredients of drugs, and so forth, in high content, to develop afine granule keeping enteric dissolution, a disintegrability anddissolution and suitable strength, and to develop an orallydisintegrable preparation containing such a fine granule, being a fastdisintegration type, showing superior oral disintegrability anddissolution and having suitable strength (hardness) so that it will notbe damaged through production processes or handling.

[0017] In particular, there is a need to combine an acid-labilephysiologically active substance, with basic inorganic salts and soforth for stability, and further to coat with coating layers such as anenteric layer. In such cases, it is an important problem to produce ansmall enteric coated fine granule, even though it contains theacid-labile physiologically active substance in high concentration andin high content.

DISCLOSURE OF INVENTION

[0018] The present invention relates to:

[0019] [1] an orally disintegrable tablet which comprises (i) finegranules having an average particle diameter of 400 μm or less, whichfine granules comprise a composition coated by an enteric coating layer,said composition having 10 weight % or more of an acid-labilephysiologically active substance and (ii) an additive;

[0020] [2] an orally disintegrable tablet of the above [1], wherein theaverage particle diameter of the fine granules is 300 to 400 μm;

[0021] [3] an orally disintegrable tablet of the above [1], wherein thefine granules further comprise a basic inorganic salt;

[0022] [4] an orally disintegrable tablet of the above [1], wherein theadditive comprises a water-soluble sugar alcohol;

[0023] [5] an orally disintegrable tablet of the above [1], wherein thecomposition coated by an enteric coating layer is further coated by acoating layer which comprises a water-soluble sugar alcohol;

[0024] [6] an orally disintegrable tablet of the above [4], wherein theadditive comprises (i) crystalline cellulose and/or (ii) low-substitutedhydroxypropyl cellulose;

[0025] [7] an orally disintegrable tablet of the above [1], wherein theparticle diameter of the fine granules is practically 425 μm or less;

[0026] [8] an orally disintegrable tablet of the above [1], wherein theparticle diameter of the fine granules is practically 400 μm or less;

[0027] [9] an orally disintegrable tablet of the above [1], wherein theacid-labile physiologically active substance is a benzimidazole compoundor a salt thereof;

[0028] [10] an orally disintegrable tablet of the above [9], wherein thebenzimidazole compound is lansoprazole;

[0029] [11] an orally disintegrable tablet of the above [3], wherein thebasic inorganic salt is a salt of magnesium and/or a salt of calcium;

[0030] [12] an orally disintegrable tablet of the above [1], wherein thecomposition comprises a core being coated by a benzimidazole compoundand a basic inorganic salt, said core comprising crystalline celluloseand lactose;

[0031] [13] an orally disintegrable tablet of the above [12], whereinthe core comprises 50 weight % or more of lactose;

[0032] [14] an orally disintegrable tablet of the above [12], whereinthe core comprises 40 to 50 weight % of crystalline cellulose and 50 to60 weight % of lactose;

[0033] [15] an orally disintegrable tablet of the above [1], wherein thecomposition comprises 20 weight % or more of an acid-labilephysiologically active substance;

[0034] [16] an orally disintegrable tablet of the above [1], wherein thecomposition comprises 20 to 50 weight % of an acid-labilephysiologically active substance;

[0035] [17] an orally disintegrable tablet of the above [1], wherein thefine granules are produced by fluidized-bed granulation method;

[0036] [18] an orally disintegrable tablet of the above [1], wherein theenteric coating layer comprises an aqueous enteric polymer agent;

[0037] [19] an orally disintegrable tablet of the above [18], whereinthe aqueous enteric polymer agent is a methacrylate copolymer;

[0038] [20] an orally disintegrable tablet of the above [18], whereinthe enteric coating layer further comprises a sustained-release agent;

[0039] [21] an orally disintegrable tablet of the above [20], whereinthe sustained-release agent is a methacrylate copolymer;

[0040] [22] an orally disintegrable tablet of the above [20], whereinthe sustained-release agent is in an amount of 5 to 15 weight % relativeto 100 weight % of the aqueous enteric polymer agent;

[0041] [23] an orally disintegrable tablet of the above [4], wherein thewater-soluble sugar alcohol is erythritol;

[0042] [24] an orally disintegrable tablet of the above [4], wherein thewater-soluble sugar alcohol is mannitol;

[0043] [25] an orally disintegrable tablet of the above [5], wherein thewater-soluble sugar alcohol is in an amount of 5 to 97 weight % relativeto 100 weight % of the orally disintegrable tablet apart from the finegranules;

[0044] [26] an orally disintegrable tablet of the above [4], wherein thecrystalline cellulose is in an amount of 3 to 50 weight % relative to100 weight % of the tablet apart from the fine granule;

[0045] [27] an orally disintegrable tablet of the above [6], wherein thecontent of hydroxypropoxyl group in the low-substituted hydroxypropylcellulose is 7.0 to 9.9 weight %;

[0046] [28] an orally disintegrable tablet of the above [6], wherein thecontent of hydroxypropoxyl group in the low-substituted hydroxypropylcellulose is 5.0 to 7.0 weight %;

[0047] [29] an orally disintegrable tablet of the above [1], whichfurther comprises crospovidone;

[0048] [30] an orally disintegrable tablet of the above [1], wherein theoral disintegration time is one minute or less;

[0049] [31] an orally disintegrable tablet of the above [1], whichcomprises no lubricant inside the tablet;

[0050] [32] fine granules having an average particle diameter of 400 μmor less, which comprise a composition coated by an enteric coatinglayer, said composition having (i) 25 weight % or more of an acid-labilephysiologically active substance and (ii) a basic inorganic salt;

[0051] [33] fine granules of the above [32], wherein the averageparticle diameter of the fine granules is 300 to 400 μm;

[0052] [34] fine granules of the above [32], wherein the particlediameter of the fine granules is practically 425 μm or less;

[0053] [35] fine granules of the above [32], wherein the particlediameter of the fine granules is practically 400 μm or less;

[0054] [36] fine granules of the above [32], wherein the acid-labilephysiologically active substance is a benzimidazole compound or a saltthereof;

[0055] [37] fine granules of the above [36], wherein the benzimidazolecompound is lansoprazole;

[0056] [38] fine granules of the above [32], wherein the basic inorganicsalt is a salt of magnesium and/or a salt of calcium;

[0057] [39] fine granules of the above [32], wherein the compositioncomprises a core being coated by a benzimidazole compound and a basicinorganic salt, said core comprising crystalline cellulose and lactose;

[0058] [40] fine granules of the above [39], wherein the core comprises50 weight % or more of lactose;

[0059] [41] fine granules of the above [32], wherein the compositioncomprises 25 to 40 weight % of an acid-labile physiologically activesubstance;

[0060] [42] fine granules of the above [32], which are produced byfluidized-bed granulation method;

[0061] [43] fine granules of the above [32], wherein the enteric coatinglayer comprises an aqueous enteric polymer agent;

[0062] [44] fine granules of the above [43], wherein the aqueous entericpolymer agent is a methacrylate copolymer;

[0063] [45] fine granules of the above [43], wherein the enteric coatinglayer further comprise a sustained-release agent;

[0064] [46] fine granules of the above [45], wherein thesustained-release agent is a methacrylate copolymer;

[0065] [47] fine granules of the above [45], wherein thesustained-release agent is in an amount of 5 to 15 weight % relative to100 weight % of the aqueous enteric polymer agent;

[0066] [48] fine granules of the above [32], wherein the enteric coatinglayer is in an amount of 50 to 70 weight % relative to 100 weight % ofthe fine granules;

[0067] [49] a tablet, granule, fine granule, capsule, effervescent orsuspension preparation which comprises the fine granules of the above[32], and so forth.

[0068] In the present specification, “coating” means also partialcoating and adhesion or adsorption in addition to coating the wholesurface of an object (e.g., core) which is to be coated.

[0069] “Spherical” means also forms having a curved surface such asforms having elliptic cross sections, and forms in the shapes ofeggplants and drops in addition to spheres.

[0070] “Average particle diameter” means volume based distributionmedian diameter (median diameter: 50% particle diameter from cumulativedistribution), unless otherwise specified. It can be measured by, forexample, a laser diffraction particle distribution measurement method.Concretely exemplified is a method using Raser Diffraction Analyzer,type: HEROS RODOS [trade name; manufactured by Sympatec (Germany)].

[0071] “An orally disintegrable tablet” of the present inventioncomprises (i) fine granules having an average particle diameter of 400μm or less, which fine granules comprise a composition coated by anenteric coating layer, said composition having 10 weight % or more of anacid-labile physiologically active substance and (ii) an additive.

[0072] In the present invention, “fine granules having an averageparticle diameter of 400 μm or less, which fine granules comprise acomposition coated by an enteric coating layer, said composition having10 weight % or more of an acid-labile physiologically active substance”have an average particle diameter of about 400 μm or less, in order thatroughness is not felt in the mouth. Preferably, the average particlediameter of the fine granules is 300 to 400 μm.

[0073] Aside from the average particle diameter of the above “finegranules”, regarding the maximum particle size, the particle diameter ispractically 425 μm or less, and preferably practically 400 μm or less.Preferably, the particle diameter is practically 300 to 425 μm, morepreferably 300 to 400 μm.

[0074] “Practically” as used in “the particle diameter is practically425 μm or less” and “the particle diameter is practically 400 μm orless” means that the particles may include a small quantity (about 5weight % or less) of particles whose particle diameter is out of abovedescribed range, to include the inevitably contaminant particles.

[0075] “An acid-labile physiologically active substance” includes acompound being unstable in an acidic region and/or a compoundinactivated by an acid, especially a pharmaceutical ingredient.Concretely mentioned are vitamins such as vitamin B₁₂, fursultiamine,folic acid, vitamin A, vitamin D, as well as a known benzimidazolecompound having an antiulcer activity of the formula (I) below, or asalt thereof.

[0076] wherein ring A may be substituted; R¹, R³ and R⁴ are the same ordifferent and each is a hydrogen, an alkyl or an alkoxy;

[0077] R² is C₁₋₄ alkyl which may be substituted by a substituent(s)selected from the group consisting of halogen, hydroxy and C₁₋₄ alkoxy;and n is 0 or 1.

[0078] In the above formula (I), “substituent(s)” of the “substitutedring A” include, for example, halogen, C₁₋₁₀ alkyl which may besubstituted, C₃₋₇ cycloalkyl which may be substituted, C₂₋₁₆ alkenylwhich may be substituted, C₁₋₁₀ alkoxy which may be substituted, cyano,carboxy, C₁₋₇ alkoxycarbonyl, C₁₋₄ alkoxycarbonyl-C₁₋₄ alkyl, carbamoyl,carbamoyl-C₁₋₄ alkyl, hydroxy, hydroxy-C₁₋₇ alkyl, C₁₋₆ acyl,carbamoyloxy, nitro, C₂₋₆ acyloxy, C₆₋₁₂ aryl, C₆₋₁₂ aryloxy, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, etc.

[0079] The “substituent” of the above “C₁₋₁₀ alkyl which may besubstituted”, “C₃₋₇ cycloalkyl which may be substituted”, or “C₂₋₁₆alkenyl which may be substituted” includes, for example, (1) halogen,(2) nitro, (3) amino which may be substituted by 1 or 2 of C₁₋₄ alkyland C₁₋₄ acyl, etc., (4) amidino, (5) guanidino, (6) carbamoyl, etc. Thenumber of these substituent is 1 to 3.

[0080] The “substituent” of the above “C₁₋₁₀ alkoxy which may besubstituted” includes, for example, (1) halogen, (2) nitro, (3) aminowhich may be substituted by 1 or 2 of C₁₋₄ alkyl and C₁₋₄ acyl, etc.,(4) amidino, (5) guanidino, etc. The number of these substituent is 1 to3.

[0081] The above “C₁₋₆ acyl” includes, for example, C₂₋₆ alkanoyl suchas formyl, acetyl, propionyl, etc.

[0082] The above “C₁₋₄ acyl” includes, for example, formyl and C₂₋₄alkanoyl such as acetyl, propionyl, etc.

[0083] The above “C₂₋₆ acyloxy” includes, for example, C₂₋₆ alkanoyloxysuch as acetyloxyl, etc.

[0084] The above “C₆₋₁₂ aryl” includes, for example, phenyl, naphthyl,etc.

[0085] The above “C₆₋₁₂ aryloxy” includes, for example, phenoxy,naphthyloxy, etc.

[0086] The “alkyl” for R¹, R³ or R⁴ includes, for example, astraight-chain or branched C₁₋₁₀ alkyl such as methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. Amongothers, preferred is a straight-chain or branched C₁₋₆ alkyl. Morepreferred is a straight-chain or branched C₁₋₃ alkyl.

[0087] The “alkoxy” for R¹, R³ or R⁴ includes, for example, C₁₋₁₀ alkoxysuch as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy,heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy,etc. Among others, preferred is C₁₋₆ alkoxy. More preferred is C₁₋₃alkoxy.

[0088] The “C₁₋₄ alkyl” of the “C₁₋₄ alkyl which may be substituted by asubstituent(s) selected from the group consisting of halogen, hydroxyand C₁₋₄ alkoxy” for R² includes, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0089] The “C₁₋₄ alkoxy” of the above “C₁₋₄ alkyl which may besubstituted by a C₁₋₄ alkoxy” includes, for example, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy,etc.

[0090] The number of the substituents which the “C₁₋₄ alkyl” has ispreferably 1 to 3.

[0091] Salts of the benzimidazole compound include pharmaceuticallyacceptable salts such as alkali metal salts, e. g., sodium salts andpotassium salts, alkaline earth metal salts e. g., calcium salts andmagnesium salts, etc.

[0092] Such benzimidazole compounds having an antiulcer activity, orsalts thereof include, for example, a compound or a salt thereofdisclosed in JP-A-52-62275, JP-A-54-141783, JP-A-57-53406,JP-A-58-135881, JP-A-58-192880, JP-A-59-181277, JP-A-61-50978,JP-A-62-116576, JP-A-62-277322, JP-A-62-258320, JP-A-62-258316,JP-A-64-6270, JP-A-64-79177, JP-A-5-59043, JP-A-62-111980,JP-A-5-117268, EP-A-166287, EP-A-519365, and so forth.

[0093] The “physiologically active substance” of the present inventionpreferably is a benzimidazole compound or a salt thereof such aslansoprazole, omeprazole, rabeprazole, pantoprazole, perprazole,leminoprazole, TU-199, etc. Preferred is lansoprazole and omeprazole,etc. More preferred is lansoprazole.

[0094] The amount of the “acid-labile physiologically active substance”in the “composition” is, for example, about 10 weight % or more,preferably about 20 weight % or more, more preferably about 23 weight %or more, especially preferably about 25 weight % or more. Among others,preferred is 20 to 50 weight %.

[0095] In the “composition”, a basic inorganic salt is preferablyincorporated with the acid-labile physiologically active substance.

[0096] The “basic inorganic salt” includes, for example, a basicinorganic salt of sodium, potassium, magnesium and/or calcium,preferably a basic inorganic salt of magnesium and/or calcium. Amongothers, preferred is a basic inorganic salt of magnesium.

[0097] The basic inorganic salt of sodium includes, for example, sodiumcarbonate, sodium hydrogencarbonate, etc.

[0098] The basic inorganic salt of potassium includes, for example,potassium carbonate, potassium hydrogencarbonate, etc.

[0099] The basic inorganic salt of magnesium includes, for example,heavy magnesium carbonate, magnesium carbonate, magnesium oxide,magnesium hydroxide, magnesium metasilicate aluminate, magnesiumsilicate, magnesium aluminate, synthetic hydrotalcite[Mg₆Al₂(OH)₁₆.CO₃.4H₂O], aluminum magnesium hydroxide[2.5MgO.Al₂O₃.xH₂O], etc. Among others, preferred is heavy magnesiumcarbonate, magnesium carbonate, magnesium oxide, magnesium hydroxide,etc.

[0100] The basic inorganic salt of calcium includes, for example,precipitated calcium carbonate, calcium hydroxide, etc.

[0101] The preferable examples of the “basic inorganic salt” includeheavy magnesium carbonate, magnesium carbonate, magnesium oxide,magnesium hydroxide, etc.

[0102] Such basic inorganic salt of magnesium or calcium, etc. has abasic pH (not less than 7) when it is in the form of a 1% aqueoussolution or suspension.

[0103] Two or more of these basic inorganic salts (preferably a basicinorganic salt of magnesium, a basic inorganic salt of calcium, etc.)can be used as a mixture in a given ratio. The amount of the basicinorganic salt to be used is appropriately selected depending on thekind of the basic inorganic salt and is, for instance, about 0.3 to 200weight %, preferably about 1 to 100 weight %, more preferably about 10to 50 weight %, especially preferably about 20 to 40 weight % relativeto the benzimidazole compound or a salt thereof.

[0104] The “composition” may contain water-soluble polymers, thefollowing binders, lubricants, and excipients, etc. in common use aspharmaceutical materials. The amount of such water-soluble polymers,binders, lubricants, and excipients is selected from amounts commonlyemployed in the manufacture of preparations in general dosage forms.

[0105] The “water-soluble polymer” includes, for example, awater-soluble polymer which is soluble in ethanol (i.e., anethanol-soluble water-soluble polymer) such as a cellulose derivative(e.g., hydroxypropyl cellulose, which may be referred to as “HPC”hereinafter), poly(vinylpyrrolidone), etc.; a water-soluble polymerwhich is insoluble in ethanol (i.e., an ethanol-insoluble water-solublepolymer) such as a cellulose derivative (e.g., hydroxypropylmethylcellulose, which may be referred to as “HPMC” hereinafter, methylcellulose, carboxymethyl cellulose sodium, etc.), sodium polyacrylate,polyvinyl alcohol, sodium alginate, and guar gum, etc.

[0106] When such water-soluble polymers are used, the dissolution ofdrugs (physiologically active substances) can be controlled by employingthem in combination with the ethanol-soluble water-soluble polymer andethanol-insoluble water-soluble polymer or by employing them incombination with some water-soluble polymers having different viscosity.

[0107] In the present invention, the “water-soluble polymer” ispreferably, a cellulose derivative such as HPC, HPMC, and methylcellulose, and polyvinyl alcohol. More preferred is a cellulosederivative such as HPC, HPMC.

[0108] The “HPC” contains, for example, about 53.4 to 77.5 weight %,more preferably about 60 to 70 weight %, of hydroxypropoxyl group. Theviscosity of 2 weight % aqueous solution of HPC at 20° C. is usuallyabout 1 to 150,000 cps (centipoise). As the above HPC, hydroxypropylcellulose defined in Japanese Pharmacopoeia may be employed.Hereinafter, all viscosity of HPC is a value of 2 weight % aqueoussolution at 20° C.

[0109] The “HPMC” is a mixed ether which is connected by a methoxy groupand a hydroxypropoxy group. The content of the methoxy group of HPMC is,for example, about 19 to 30 weight %. The content of the hydroxypropoxygroup is, for example, about 4 to 12 weight %. The viscosity of 2 weight% aqueous solution of HPMC at 20° C. is usually about 1 to 40,000centistokes. As such HPMC may be employed hydroxypropylmethyl cellulose2208 defined by Japanese Pharmacopoeia, hydroxypropylmethyl cellulose2906 defined by Japanese Pharmacopoeia, hydroxypropylmethyl cellulose2910 defined by Japanese Pharmacopoeia, and so forth. Hydroxypropylcellulose(s) may be employed alone or in admixture of two or morethereof.

[0110] The content of the water-soluble polymer such as HPC and/or HPMCis usually about 0.1 to 50 weight %, preferably about 1 to 30 weight %,as against the whole “composition” containing the physiologically activesubstance, in order to control the dissolution of the physiologicallyactive substance in the composition containing the physiologicallyactive substance and retain a high content of the physiologically activesubstance.

[0111] The above “enteric coating layer” which coats the “compositionhaving 10 weight % or more of an acid-labile physiologically activesubstance” includes, for example, an aqueous enteric polymer agent suchas cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulosephthalate (hereinafter, referred to as HP-55), hydroxymethyl celluloseacetate succinate, methacrylate copolymer [e.g., Eudragit L30D-55 etc.(trade name; manufactured by Rohm GmbH (Germany)), KollICoat MAE30DP(trade name; manufactured by BASF (Germany)), Polyquid PA-30 (tradename; manufactured by SanyoKasei (Japan)), etc.],carboxymethylcellulose, shellac, etc.; a sustained-release agent such asmethacrylate copolymer [e.g., Eudragit NE30D (trade name), EudragitRL30D (trade name), Eudragit RS30D (trade name), etc.]; a water-solublepolymer; plasticizers such as triethyl citrate, polyethylene glycol,acetylated monoglyceride, triacetin, castor oil, etc. and mixturesthereof.

[0112] The “aqueous enteric polymer agent” is preferably a methacrylatecopolymer. The “sustained-release agent” is preferably a methacrylatecopolymer.

[0113] The “sustained-release agent” is used in an amount of 5 to 30weight %, preferably 5 to 15 weight %, relative to 100 weight % of the“aqueous enteric polymer agent”. The “plasticizers” is used in an amountof 5 to 30 weight % relative to 100 weight % of the “aqueous entericpolymer agent”.

[0114] The “additives” of the “orally disintegrable tablet whichcomprises (i) fine granules having an average particle diameter of 400μm or less, which fine granules comprise a composition coated by anenteric coating layer, said composition having 10 weight % or more of anacid-labile physiologically active substance and (ii) an additive” maybe ones commonly employed as pharmaceutical materials. The amount ofsuch additives to be used is selected from amounts commonly employed inthe manufacture of preparations in general dosage forms.

[0115] The “additives” include, for example, a water-soluble sugaralcohol, a crystalline cellulose, a low-substituted hydroxypropylcellulose, as well as, binders, acids, foaming agents, artificialsweeteners, flavorants, lubricants, colorants, stabilizers, excipients,disintegrants, and so forth.

[0116] The “water-soluble sugar alcohol” means a water-soluble sugaralcohol which needs water in an amount of less than 30 ml when 1 g ofwater-soluble sugar alcohol is added to water and dissolved within about30 minutes at 20° C. by strongly shaking every 5 minutes for 30 seconds.

[0117] The “water-soluble sugar alcohol” includes, for example,sorbitol, mannitol, maltitol, reduced starch saccharide, xylitol,reduced paratinose, erythritol, etc. Two or more of these water-solublesugar alcohols can be used as a mixture in a given ratio.

[0118] The “water-soluble sugar alcohol” is preferably mannitol, xylitoland erythritol. More preferred is mannitol and erythritol. Especiallypreferred is mannitol. As erythritol, one that is produced byfermentation with yeasts using glucose as the starting material, andthat has a particle size of at most 50 mesh is used. Such erythritol isavailable on the market, e.g. as manufactured by Nikken Chemical Co.,Ltd. (Japan).

[0119] The “water-soluble sugar alcohol” is usually employed in anamount of about 5 to 97 weight %, preferably about 10 to 90 weight %relative to 100 weight % of the orally disintegrable tablet apart fromthe fine granules, in order to obtain sufficient strength of thepreparation and sufficient disintegration or dissolution in the oralcavity.

[0120] For example, mannitol or erythritol is usually employed in anamount of about 5 to 90 weight %, preferably about 10 to 80 weight %,more preferably about 20 to 80 weight %, especially preferably about 50to 80 weight % relative to 100 weight % of the orally disintegrabletablet apart from the fine granules.

[0121] The “crystalline cellulose” includes refined one having partiallya-cellulose depolymerization. Such crystalline cellulose includes onecalled microcrystalline cellulose. Examples of the “crystallinecellulose” include CEOLUS KG801, avicel PH101, avicel PH102, avicelPH301, avicel PH302, avicel RC-591 (crystalline cellulose carmellosesodium), etc. Among these, preferably employed is CEOLUS KG801 which isalso called crystalline cellulose of high compressibility. Two or moreof the crystalline cellulose can be used as a mixture in a given ratio.Such crystalline cellulose is available on the market, for example, asmanufactured by Asahi Chemical Co., Ltd. (Japan).

[0122] The “crystalline cellulose” is used, for instance, in an amountof about 3 to 50weight %, preferably about 5 to 40weight %, morepreferably about 5 to 20 weight % relative to 100 weight % of the orallydisintegrable tablet apart from the fine granules.

[0123] The “low-substituted hydroxypropyl cellulose” means alow-substituted hydroxypropyl cellulose wherein the content ofhydroxypropoxyl group in the hydroxypropyl cellulose (hereinafter, maybe abbreviated to the “content of HPC group”) is about 5.0 to 9.9 weight%, preferably a low-substituted hydroxypropyl cellulose wherein thecontent of HPC group is about 5.0 to 7.0 weight %, a low-substitutedhydroxypropyl cellulose wherein the content of HPC group is about 7.0 to9.9 weight %, and so forth.

[0124] The “low-substituted hydroxypropyl cellulose wherein the contentof HPC group is about 7.0 to 9.9% includes, for example, LH-22, LH-32and mixtures thereof, which are commercially available [Shin-EtsuChemical Co., Ltd. (Japan)]. Also, they can be produced in accordancewith per se known methods, for example, methods described in JP-B-8253100 or analogous thereto.

[0125] The low-substituted hydroxypropyl cellulose wherein the contentof HPC group is about 5.0 to 7.0% includes, for example, LH-23, LH-33and mixtures thereof, described in the following Reference Examples.They can be produced in accordance with per se known methods, forexample, methods described in JP-B-82 53100 or analogous thereto.

[0126] At first, alkaline cellulose containing free alkaline andpropylene oxide is reacted to obtain the crude low-substitutedhydroxypropyl cellulose containing free alkaline.

[0127] Concretely, for example, raw material pulp such as wood pulp andcotton leader is immersed in about 10 to 50% concentration of an aqueoussolution of sodium hydroxide, and pressed to obtain alkaline celluloseof which NaOH/cellulose ratio is about 0.1 to 1.2 (ratio by weight).Next, crude low-substituted hydroxypropyl cellulose containing freealkaline is obtained by reacting the resulting alkaline cellulose andpropylene oxide with stirring at about 20 to 90° C. for about 2 to 8hours. Propylene oxide is used in an amount so that the content ofhydroxypropoxyl group in the desired low-substituted hydroxypropylcellulose can be 5 or more weight % to less than 7 weight % (in case ofthe low-substituted hydroxypropyl cellulose wherein the content of HPCgroup is about 5.0 to 7.0 weight %), 7 or more weight % to less than 9.9weight % (in case of the low-substituted hydroxypropyl cellulose whereinthe content of HPC group is about 7.0 to 9.9 weight %).

[0128] The crude low-substituted hydroxypropyl cellulose containing freealkaline is dispersed in water or hot water containing about 5 to 80% ofacid necessary to neutralize all the alkaline, and a part of the crudelow-substituted hydroxypropyl cellulose containing free alkaline isdissolved therein. Acid is further added to neutralize the remainingalkaline.

[0129] After the neutralization, some processes such as drainage, dryingand grinding are performed in accordance with conventional methods toobtain the desired low-substituted hydroxypropyl cellulose.

[0130] The particle diameter of “the low-substituted hydroxypropylcelluloses wherein the content of hydroxypropoxyl group is 5.0 to 7.0weight %” to be used in the present invention is, for example, about 5to 60 μm, preferably about 10 to 40 μm, as a average particle diameter.

[0131] In the above ranges, in case that low-substituted hydroxypropylcelluloses (L-HPC) having a relatively large particle diameter (forexample, L-HPC having about 26 to 40 μm of the average particlediameter) is employed, a pharmaceutical preparation superior indisintegrability can be produced. On the other hand, in case that L-HPChaving a relatively small particle diameter (for example, L-HPC havingabout 10 to 25 μm of the average particle diameter) is employed, apharmaceutical preparation superior in strength of the preparation canbe produced. Accordingly, the particle diameter of L-HPC can be suitablyselected according to the characteristics of the desired pharmaceuticalpreparation.

[0132] The “low-substituted hydroxypropyl cellulose wherein the contentof HPC group is 5.0 to 7.0 weight %” or the “low-substitutedhydroxypropyl cellulose wherein the content of HPC group is 7.0 to 9.9%”is usually employed in an amount of about 3 to 50 weight %, preferablyabout 5 to 40 weight %, relative to 100 weight % of the orallydisintegrable tablet apart from the fine granules, in order to obtainsufficient oral disintegrability and sufficient strength of thepreparation.

[0133] The “binders” include, for example, hydroxypropyl cellulose,hydroxypropylmethylcellulose, crystalline cellulose, a starch(pregelatinized starch), polyvinylpyrrolidone, gum arabic powder,gelatin, pullulan, low-substituted hydroxypropyl cellulose, etc. The useof crystalline cellulose as the binders provides a solid preparationwhich exhibits more excellent strength of a preparation while retainingexcellent disintegration and dissolution in the oral cavity.

[0134] The “acids” include, for example, citric acid (e.g., citric acidanhydrous), tartaric acid, malic acid, etc.

[0135] The “foaming agents” include, for example, sodium hydrogencarbonate, etc.

[0136] The “artificial sweeteners” include, for example, saccharinsodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, etc.

[0137] The “flavorants” include synthetic flavorants or naturalflavorants, such as lemon, lime, orange, menthol, strawberry, etc.

[0138] The “lubricants” include, for example, magnesium stearate,sucrose fatty acid ester, polyethyleneglycol, talc, stearic acid, etc.

[0139] The “colorants” include, for example, various food colorants suchas Food Yellow No. 5, Food RED No.2, Food Blue No.2, etc., food lakes,red iron oxide, etc.

[0140] The “stabilizers” include, for example, the above-mentioned“basic inorganic salt”.

[0141] The “excipients” include, for example, lactose, sucrose,D-mannitol, starch, corn starch, crystalline cellulose, light silicicanhydride, titanium oxide, etc.

[0142] The “disintegrants” include those conventionally used in thepharmaceutical field, such as (1) crospovidone, (2) super disintegrantssuch as croscarmellose sodium [FMC-Asahi Chemical Co., Ltd. (Japan)],carmellose calcium [Gotoku Chemical(Yakuhin), (Japan)], (3)carboxymethylstarch sodium [e.g., Matsutani Chemical Co., Ltd. (Japan)],(4) low-substituted hydroxypropylcellulose [e.g., Shin-Etsu ChemicalCo., Ltd. (Japan)], (5) corn starch, etc. Among others, preferred is,for example, crospovidone.

[0143] The “crospovidone” includes polyvinylpolypyrrolidone (PVPP),1-vinyl-2-pyrrolidinone homopolymer, 1-ethenyl-2-pyrrolidinonehomopolymer, etc, such as Kollidon CL [manufactured by BASF (Germany)],Polyplasdone XL [manufactured by ISP Ltd. (Japan)], Polyplasdone XL-10[manufactured by ISP Ltd. (Japan)], Polyplasdone INF-10 [manufactured byISP Ltd. (Japan)], etc. Usually crospovidone having a molecular weightof at least 1,000,000 is used.

[0144] Two or more of these disintegrants can be as a mixture in a givenratio. For example, (i) crospovidone solely, or (ii) crospovidone andanother disintegrant(s) is preferably employed.

[0145] The “disintegrants” are used, for instance, in an amount of about1 to 15 weight %, preferably about 1 to 10 weight %, more preferablyabout 3 to 7 weight %, relative to 100 weight % of the orallydisintegrable tablet apart from the fine granules.

[0146] In the present invention, the “fine granules” may contain, forexample, titanium oxide as a masking agent.

[0147] The diameter of the “orally disintegrable tablet” of the presentinvention is about 5 to 20 mm, preferably about 7 to 15 mm, morepreferably about 8 to 13 mm.

[0148] The “orally disintegrable tablet” may comprise no lubricantinside the tablet.

[0149] The “orally disintegrable tablet” of the present inventionexhibits fast disintegrability or dissolubility in the oral cavity, andalso an appropriate strength of preparation.

[0150] The oral disintegration time of the “orally disintegrable tablet”of the present invention (the time for healthy male or female adults tocomplete disintegration by buccal saliva) is one minute or less, usuallyabout 50 seconds or less, preferably about 40 seconds or less, morepreferably about 30 seconds or less.

[0151] The strength of the “orally disintegrable tablet” of the presentinvention (measurement with a tablet hardness tester) is usually about 1to 20 kg, preferably about 2 to 15 kg, more preferably 3 to 8 kg.

[0152] In the above-mentioned fine granules, “fine granules having anaverage particle diameter of 400 μm or less, which comprise acomposition coated by an enteric coating layer, said composition having(i) 25 weight % or more of an acid-labile physiologically activesubstance and (ii) a basic inorganic salt” are novel.

[0153] The “fine granules” have an average particle diameter of about400 μm or less, preferably 350 μm or less. Preferably, the averageparticle diameter of the fine granules is 300 to 400 μm. Aside from theaverage particle diameter of the “fine granules”, regarding the maximumparticle size, the particle diameter is practically 425 μm or less, andpreferably practically 400 μm or less. Preferably, the particle diameteris practically 300 to 400 μm or less.

[0154] Regarding the fine granule of the present invention, thedissolution of the physiologically active substance can be controlled byformulating the coat (coating layer) to have different viscosity orcontent of the water-soluble polymer (e.g., HPC, HPMC and so forth) orby formulating the coat to have a controlled ratio of theethanol-soluble water-soluble polymer (e.g., HPC) and theethanol-insoluble water-soluble polymer (e.g., HPMC). The dissolution ofthe physiologically active substance is not very influenced byliquidity, which can be suitably controlled.

[0155] As a pharmaceutical preparation which comprises the “finegranules” of the present invention, there may be employed, for example asolid preparation such as tablet, granule, fine granule, capsule,effervescent, etc; a liquidpreparation such as suspension preparation,etc. Among others, preferred is a tablet, more preferred is an orallydisintegrable tablet.

[0156] When the “fine granule” of the present invention is used for atablet except for an orally disintegrable tablet, the diameter of thetablet is about 5 to 10 mm, preferably about 5 to 8 mm. When the finegranule of the present invention is used for a capsule, the size of thecapsule is preferably a #2 capsule or less.

[0157] The “orally disintegrable tablet” of the resent invention and the“pharmaceutical preparation which comprises the fine granules of thepresent invention” may contain a foaming component to impart arefreshing feeling at administration. Also, with an effervescentcomprising the foaming component, the dissolution can be preciselycontrolled compared to the case of a fine granule alone. As the foamingcomponent, various compounds can be employed as long as safety is notinterfered with. Examples of the foaming component include alkalinemetal carbonate (e.g., sodium carbonate, potassium carbonate, etc.),alkaline metal hydrogencarbonate (e.g., sodium hydrogencarbonate,potassium hydrogencarbonate, etc.) and ammonium carbonate and so forth.The foaming component(s) may be employed alone or in an admixture of twoor more thereof. The preferable foaming component includes sodiumcarbonate, sodium hydrogencarbonate, ammonium carbonate and so forth.The ratio of the foaming component can be selected within the range inwhich it is possible to impart the foam, for example, about 10 to 2500weight %, preferably about 50 to 2000 weight % (e.g., about 75 to 1500weight %), more preferably about 100 to 1000 weight %, relative to 100weight % of the fine granule.

[0158] In employing the effervescent and the fine granule having smallparticle diameter, it is advantageous to quickly prepare a homogeneousaqueous solution or suspension, and to maintain the dispersed condition.But, in case that the particle diameter is too small, the problem tendsto occur that the fine granule adheres to the wall of machine by staticelectricity during production processes.

[0159] The specific volume of the above fine granule is about 3 ml/g orless, preferably about 2 ml/g or less. In order to maintain thehomogeneous condition of the fine granule in the suspension obtained byadding the foaming agent composition, the specific volume can besuitably selected in the above range according to the specific gravity(specific volume) of the dispersion medium.

[0160] The “composition” in the present invention can be produced by aknown granulation method.

[0161] The “granulation method” includes, for example, rollinggranulation method (e.g., centrifugal rolling granulation, etc.),fluidized-bed granulation (e.g., rolling fluidized-bed granulation,fluidized granulation, etc.), stirring granulation and so forth. Amongothers, preferred is fluidized-bed granulation method, more preferred isrolling fluidized-bed granulation method.

[0162] Concrete example of the “rolling granulation method” includes amethod using “CF apparatus” manufactured by Freund Industrial Co., Ltd.(Japan) and so forth. Concrete examples of the “rolling fluidized-bedgranulation method” include methods using “SPIR-A-FLOW”, “multi plex”manufactured by Powrex Corp. (U. S. A.), “New-Marumerizer” manufacturedby Fuji Paudal Co., Ltd. (Japan), and so forth. The method for sprayingthe mixture can be suitably selected in accordance with the kind ofgranulator, and may be, for example, any one of a top spray method, abottom spray method, a tangential spray method, and so forth. Amongothers, a tangential spray method is preferred.

[0163] The “composition” in the present invention can be produced inaccordance with, for example, a method which comprises coating a corecomprising crystalline cellulose and lactose with an acid-labilephysiologically active substance.

[0164] For example, employed is a method described in JP-A-5-92918(coating method), which comprises coating a core comprising crystallinecellulose and lactose with an acid-labile physiologically activesubstance, if necessary together with a basic inorganic salt, binders,lubricants, excipients, a water-soluble polymer, etc. (hereinafter, maybe abbreviated to “coating layer”). For example, employed is a methodwhich comprises coating a core with an acid-labile physiologicallyactive substance and a basic inorganic salt, and then further withbinders, lubricants, excipients, a water-soluble polymer, etc.

[0165] The average particle diameter of the “cores” is about 250 μm orless, preferably about 50 to 250 μm, more preferably about 100 to 250μm, especially preferably about 100 to 200 μm. The “cores” having theabove average particle diameter include particles which all pass througha #50 sieve (300 μm), particles where about 5 w/w % or less of the totalremain on a #60 sieve (250 μm), and particles where about 10 w/w % orless of the total pass through a #282 sieve (53 μm). The specific volumeof the “core” is about 5 ml/g or less, preferably about 3 ml/g or less.

[0166] Examples of the “core” include

[0167] (1) a spherical granulated product comprising crystallinecellulose and lactose, (2) a spherical granulated product being about150 to 250 μm and comprising crystalline cellulose (avicel SP,manufactured by Asahi Chemical Co., Ltd. (Japan)), (3) a stirringgranulated product being about 50 to 250 μm and comprising lactose (9parts) and a starch (1 part), (4) a micro particle being about 250 μm orless classified as a spherical granule comprising micro crystallinecellulose described in JP-A-61-213201, (5) a processed product such aswax formed to a sphere by spraying or melting granulation, (6) aprocessed product such as gelatin beads comprising oil component, (7)calcium silicate, (8) starch, (9) a porous particle such as chitin,cellulose, chitosan, etc, and (10) a bulk product such as granulatedsugar, crystalline lactose or sodium chloride, and processedpreparations thereof. Further, these cores may be produced in accordancewith per se known grinding method or granulation method, and sifted toprepare the particles having the desired particle diameter.

[0168] The above “spherical granulated product comprising crystallinecellulose and lactose” includes, for example (i) a spherical granulatedproduct being 100 to 200 μm and comprising crystalline cellulose (3parts) and lactose (7 parts) [e.g., Nonpareil 105 (70-140) (particlediameter of 100 to 200 μm), manufactured by Freund Industrial Co., Ltd.(Japan)], (ii) a spherical granulated product being about 150 to 250 μmand comprising crystalline cellulose (3 parts) and lactose (7 parts)[e.g., Nonpareil NP-7:3, manufactured by Freund Industrial Co., Ltd.(Japan)], (iii) a spherical granulated product being 100 to 200 μm andcomprising crystalline cellulose (4.5 parts) and lactose (5.5 parts)[e.g., Nonpareil 105T (70-140) (particle diameter of 100 to 200 μm),manufactured by Freund Industrial Co., Ltd. (Japan)], (iv) a sphericalgranulated product being about 150 to 250 μm and comprising crystallinecellulose (5 parts) and lactose (5 parts) [e.g., Nonpareil NP-5:5,manufactured by Freund Industrial Co., Ltd. (Japan)], and so forth.

[0169] In order to produce a pharmaceutical preparation which issuperior in dissolution while retaining suitable strength, the “core”includes, for example, preferably the spherical granulated productcomprising crystalline cellulose and lactose, more preferably thespherical granulated material comprising crystalline cellulose andlactose and containing 50 weight % or more of lactose. Among others,preferred is a core comprising 40 to 50 weight % of crystallinecellulose and 50 to 60 weight % of lactose.

[0170] As the “core” employed in the present invention, in particular,there may be employed the spherical granulated product comprisingcrystalline cellulose and lactose, more preferably the sphericalgranulated product with a diameter of about 100 to 200 μm and comprisingcrystalline cellulose (4.5 parts) and lactose (5.5 parts).

[0171] The “core” may contain the physiologically active substance suchas the above described pharmaceutical ingredient. Also, the “core” maynot contain the physiologically active substance because the release ofthe physiologically active substance can be controlled by a coatinglayer containing the physiologically active substance.

[0172] The “core” is preferably as uniform a sphere as possible, forreducing the irregularity of the coating, in addition to being a powderycore.

[0173] The ratio of the “coating layer” to the “core” can be selectedwithin the range in which it is possible to control dissolution of thephysiologically active substance and particle size of the composition,for example, usually about 50 to 400 weight % relative to 100 weight %of the core.

[0174] The coating layer may be constructed by plural layers. At leastone layer of the plural layers must contain the physiologically activesubstance. The combination of various layers such as a coating layer notcontaining the active ingredient, a base coating layer, and an entericcoating layer which constitute the coating layer can be suitablyselected.

[0175] In case that the “core” is coated, for example, the abovephysiologically active substance and the water-soluble polymer can beemployed in admixture thereof. The admixture may be a solution or adispersion, and can be prepared by using an organic solvent such aswater or ethanol or an admixture thereof.

[0176] The concentration of the water-soluble polymer in the admixturevaries according to the ratio of the physiologically active substanceand the excipients, and is usually about 0.1 to 50 weight %, preferablyabout 0.5 to 10 weight %, in order to retain the binding strength of thephysiologically active substance to the core and maintain the viscosityof the mixture so as not to reduce the workability.

[0177] Where the coating layer comprises plural layers, theconcentration of the physiologically active substance in each layer maybe changed successively or gradually by selecting for the content ratioor viscosity of the water-soluble polymer or by successive coating withmixtures varying in the ratio of the physiologically active substanceand the other excipients. In the above case, it may be coated with amixture in which the content ratio of the water-soluble polymer is outof the range of about 0.1 to 50 weight %, as long as the coating layeras a whole contains about 0.1 to 50 weight % of the water-solublepolymer. Further, in forming the inactive coat according to knownmethods, the coating layer may comprise some layers such that theinactive layer may block each layer containing the physiologicallyactive substance.

[0178] Also, in case of two or more physiologically active substancesnot suited in the compatibility, the core may be coated by employingeach mixture together or separately.

[0179] The above coated material is dried, and passed through sieves toobtain a “composition” having uniform size. Because the form of thepowder is usually according to the core, a fine granule being in theform of a rough sphere may be obtained. As the sieve may be employed,for example a #50 circular sieve (300 μm). The composition is obtainedby selecting those which pass through the #50 circular sieve.

[0180] The “fine granule” in the present invention can be produced inaccordance with in the same manner as above granulation method, forexample, a method which comprises coating the composition with anenteric coating layer, in order to protect the acid-labilephysiologically active substance or to impart enteric dissolution. Ifnecessary, the composition coated with an enteric coating layer may befurther coated by a water-soluble sugar alcohol, preferably mannitol. Insuch case, the strength of the orally disintegrable tablet comprisingfine granules is improved.

[0181] The “enteric coating layer” is preferably a layer having about 20to 70 μm, preferably about 30 to 50 μm of thickness and coating thewhole surface of the composition containing the physiologically activesubstance. Accordingly, the smaller particle diameter of thecomposition, the higher the weight % of the enteric coating layer in thewhole fine granule. In the fine granule of the present invention, the“enteric coating layer” is about 30 to 70 weight %, preferably about 50to 70 weight %, of the fine granule as a whole.

[0182] The “enteric coating layer” may be constructed by plural (e.g., 2or 3) layers. For example, employed is a method which comprises coatinga composition with an enteric coating layer having polyethyleneglycol,and then with an enteric coating layer having triethyl citrate, followedby being coated with an enteric coating layer having polyethyleneglycol.

[0183] The “orally disintegrable tablet” of the present invention can beproduced in accordance with a conventional method in the pharmaceuticalfield. Such methods include, for instance, a method which comprisesblending the “fine granules” and the “additives”, and molding, ifnecessary followed by drying. Concretely mentioned is a method whichcomprises blending the fine granules and the additives, if necessarywith water, and molding, if necessary followed by drying.

[0184] The “blending procedure” can be carried out by any of theconventional blending techniques such as admixing, kneading,granulating, etc. The above “blending procedure” is carried out, forinstance, by using an apparatus such as Vertical Granulator GV10[manufactured by Powrex Corp. (Japan)], Universal Kneader [manufacturedby Hata Iron Works Co., Ltd. (Japan)], fluidized bed granulator LAB-1and FD-3S [manufactured by Powrex Corp. (Japan)], V-shape mixer,tumbling mixer, and so forth.

[0185] Preferred example of the method for the “orally disintegrabletablet” of the present invention is a method which comprises:

[0186] (i) coating a core comprising crystalline cellulose and lactosewith an acid-labile physiologically active substance and a basicinorganic salt, followed by being coated with a coating layer comprisinga water-soluble polymer to obtain a composition,

[0187] (ii) coating the resultant composition with an enteric coatinglayer having polyethyleneglycol, and then with an enteric coating layerhaving triethyl citrate, and then with an enteric coating layer havingpolyethyleneglycol, followed by being coated by mannitol to obtain finegranule, and

[0188] (iii) blending the resultant fine granule with an additive,followed by molding.

[0189] Where the pharmaceutical preparation of the present invention,especially an orally disintegrable tablet, is one which comprises nolubricant inside the preparation or tablet, such preparation can bepreferably produced in accordance with methods described inJP-A-56-14098, Japanese Patent No. 2681601, etc. Such preparation,especially an orally disintegrable tablet, has sufficient strength. Theabove lubricant includes, for example, magnesium stearate, sucrose fattyacid ester, polyethyleneglycol, talc, stearic acid, etc.

[0190] The pharmaceutical preparations such as solid preparation (e.g.,tablets, granules, fine granules, capsules, effervescents, etc.) andliquid preparation such as suspending preparation, which comprises the“fine granules” of the present invention can be produced in accordancewith a conventional method.

[0191] The solid pharmaceutical preparation containing the “finegranules” of the present invention and the “orally disintegrable tablet”of the invention can also be produced by the wet tabletting method. Asthe above method, it is preferably employed the methods described inJP-A-5-271054 and so forth. They can also be produced by drying afterhumidification. As the above method, preferably employed are the methodsdescribed in JP-A-9-48726, JP-A-8-291051 and so forth. Namely, it iseffective to humidify before tabletting or after tabletting and then todry, in order to enhance the hardness.

[0192] The “molding procedure” can be carried out, for instance, bytabletting with a pressure of 0.5 to 3 ton/cm² preferably 1 to 2 ton/cm²by using a single-punch tabletting machine [Kikusui Seisakusho (Japan)]or a rotary type tabletting machine [Kikusui Seisakusho (Japan)] when asolid preparation is a tablet, especially an orally disintegrabletablet.

[0193] The “drying procedure” can be carried out by any of thetechniques used commonly in the art, such as vacuum drying,fluidized-bed drying, etc.

[0194] The “fine granules” of the invention can be used for apharmaceutical preparation. The pharmaceutical preparation includes, forexample, a solid preparation such as tablet, granule, fine granule,capsule, effervescent, etc.; a liquid preparation such as a suspensionpreparation, etc. Among others, a tablet is preferred. Such tabletpreferably has suitable strength so as to be stable through productionprocesses and distributions.

[0195] A solid pharmaceutical preparation comprising the fine granule ofthe invention is used for an orally disintegrable tablet and can beadministered without water or together with water.

[0196] As administration methods, there are listed (1) a method ofadministration by dissolution or disintegration together with a littlewater, or without water and with saliva in the oral cavity, not to beswallowed as it is, or (2) a method of administration with water, whereit is swallowed as it is. Also, the tablet may be administered dissolvedor disintegrated with water.

[0197] The “orally disintegrable tablet” of the present invention isadvantageously used in (a) cases where administration without water isnecessary, (b) cases of administration to a patients who have difficultyin swallowing tablets, or (c) cases of administration to the aged or tochildren where there is a fear of blocking the throat if it is in usualtablet form.

[0198] In case of the above (a), the orally disintegrable tablet ispreferably used for antipyretic agents, analgesic agents,anti-inflammatory agents, antianxiety drugs, antitussive-expectorants,anti motion sickness agents, drugs for prevention and treatment forcar-sickness, and so forth.

[0199] In case of the above (b), the orally disintegrable tablet ispreferably used for preventing and/or treating hypertension,hyperlipemia, diabetes, bronchial asthma, cerebrovascular diseases, andso forth.

[0200] The “orally disintegrable tablet” of the present invention andthe pharmaceutical preparation which comprises the “fine granules” ofthe present invention can be safely administered orally to mammals suchas mice, rats, rabbits, cats, dogs, bovines, horses, monkeys, humans,etc.

[0201] With the dosage of the “orally disintegrable tablet” of thepresent invention and the pharmaceutical preparation which comprises the“fine granules” of the present invention, varies depending on thepharmaceutically active ingredient, subject, kinds of diseases, etc.,the dosage can be selected so that the dosage of the pharmaceuticallyactive ingredient is an effective amount.

[0202] For instance, when a benzimidazole compound (I) or a salt thereofsuch as lansoprazole is employed as an acid-labile physiologicallyactive substance, especially a pharmaceutically active ingredient, the“orally disintegrable tablet” of the present invention and thepharmaceutical preparation which comprises the “fine granules” of thepresent invention is useful for treatment and prevention of digestiveulcer (e.g., gastric ulcer, duodenal ulcer, anastomotic ulcer,Zollinger-Ellison syndrome, etc), gastritis, reflux esophagitis, etc.;eradication of H. pylori; suppression of gastrointestinal bleedingcaused by digestive ulcer, acute stress ulcer and hemorrhagic gastritis;suppression of gastrointestinal bleeding caused by invasive stress(e.g., stress caused by cerebrovascular disease, head injury, failure ofmany organs, burn injury of a wide range, which necessitate alarge-scale operation necessitating the following intensive management,or intensive care); treatment and prevention of ulcer caused bynon-steroidal anti-inflammatory agent; treatment and prevention ofgastric hyperacidity and ulcer caused by postoperative stress;administration before anesthesia, etc. The dosage of the preparation peran adult (body weight: 60 kg) is about 0.5 to 1,500 mg/day, preferablyabout 5 to 150 mg/day, as a benzimidazole compound (I) or a salt thereofsuch as lansoprazole.

[0203] The “orally disintegrable tablet” of the present invention andthe pharmaceutical preparation which comprises the “fine granules” ofthe present invention can be administered once a day, or two or threetimes separately a day.

BEST MODE FOR CARRYING OUT THE INVENTION

[0204] The following Examples and Reference Examples are furtherillustrative but by no means limitative of the present invention.

[0205] Unless otherwise specifically indicated, the following “%” meansweight %.

[0206] Also, the content of the hydroxypropoxyl group is measured inaccordance with the methods described in Japanese Pharmacopoeia (13thedition).

[0207] The physical properties of the tablets and granules prepared inExamples were determined by the following test methods.

[0208] (1) Hardness Test

[0209] Determination was carried out with a tablet hardness tester[manufactured by Toyama Sangyo, Co. Ltd. (Japan)]. The test wasperformed in 10 runs and mean values were shown.

[0210] (2) Oral Disintegration Time

[0211] Time for complete disintegration only by saliva in the oralcavity was determined.

[0212] (3) Remaining Ratio

[0213] According to the 2nd method of the dissolution test defined inJapanese Pharmacopoeia, the dissolution test was performed by using 500ml of 0.1 N HCl (75 rpm) for 1 hour. Then, the enteric fine granule wascollected by means of the sieve. The content of the drug in thecollected fine granule was measured by the HPLC method. The remainingratio was calculated according to the following expression with thecontent of the drug in the tablet which is measured separately by HPLCmethod.

[0214] Remaining ratio =(Content of the drug in the collected finegranule after the dissolution test using 0.1 N HCl for 1 hour)/(Contentof the drug in the tablet)

[0215] (4) Acid-Resistance: Dissolution Using 0.1 N HCl

[0216] According to the 2nd method of the dissolution test defined inJapanese Pharmacopoeia, the dissolution test was performed by using 500ml of 0.1 N HCl (75 rpm) for hour. Then, test medium was collected andfiltered by using a 0.45 μm membrane filter. The absorbance was measuredto calculate the dissolution of the drug into 0.1 N HCl.

[0217] (5) Average Particle Diameter: Volume Based Distribution MedianDiameter (Median Diameter: 50% Particle Diameter From CumulativeDistribution)

[0218] Determination was carried out with Raser Diffraction Analyzer,type: HEROS RODOS [trade name, manufactured by Sympatec (Germany)].

EXAMPLES Example 1

[0219] (1) Production of Granules Having a Core

[0220] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] is charged with 300 g of Nonpareil105 (70-140) (particle diameter of 100 to 200 μm). With the inlet airtemperature and the temperature of the loading being controlled at 85°C. and about 28° C. respectively, the Nonpareil is coated by spraying abulk liquid of the following composition prepared in advance inaccordance with the tangential spray method at a spray rate of 20 g/min. The spraying operation is stopped when the specified amount of thebulk liquid has been sprayed, and then drying is carried out in thegranulator for 7 minutes. The resulting granules are sieved through a#60 circular sieve (250 μm) and a #100 circular sieve (150 μm) toprovide 750 g of granules having a core. Bulk liquid: Lansoprazole 300 gMagnesium carbonate 100 g L-HPC 50 g HPC (Type SSL) 100 g Water 1650 g

[0221] (2) Production of Film-Undercoated Granules Having a Core

[0222] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] is charged with 680 g of the abovegranules having a core. With the inlet air temperature and thetemperature of the loading being controlled at 70° C. and about 36° C.,respectively, an undercoating liquid of the following compositionprepared in advance is sprayed in accordance with the tangential spraymethod at a spray rate of 10 g /min. to provide 650 g offilm-undercoated granules having a core. Undercoating liquid: HPMC 32 g(Type 2910, viscosity: 3 centistokes) Talc 8 g Water 760 g

[0223] (3) Production of Enteric Coated Granules Having a Core

[0224] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] is charged with 450 g of the abovefilm-undercoated granules having a core. With the inlet air temperatureand the temperature of the loading being controlled at 65° C. and about36° C., respectively, an enteric film coating liquid of the followingcomposition prepared in advance is sprayed in accordance with thetangential spray method at a spray rate of 17 g /min. The coated powdersare dried in vacuum at 40° C. for 16 hours, and sieved through a #42circular sieve (355 μm) and a #80 circular sieve (177 μm) to provide 950g of enteric coated granules having a core. Enteric film coating liquid:Eudragit L30D-55 1078.3 g  Eudragit NE30D 138.5 g  Triethyl citrate 46.0g Glyceryl monostearate 23.1 g Talc 16.0 g Polysorbate 80  9.0 g Yellowiron oxide  0.5 g Water 2038.5 g  Sieve weight ratio #18 (850 μm) on 0%#30 (500 μm) on 0% #200 (75 μm) on 100%  #200 (75 μm) pass 0%

[0225] (4) Production of Granulated Powders

[0226] A fluidized bed granulator [manufactured by Powrex Corp. (Japan),LAB-1] is charged with 1321.2 g of erythritol [manufactured by NikkenChemical Co., Ltd. (Japan)], 360.0 g of low-substituted hydroxypropylcellulose LH-32 [hydroxypropoxyl group contents of 8.8%, manufactured byShin-Etsu Chemical Co., Ltd. (Japan)], 18.0 g of citric acid anhydrous,and 1.8 g of aspartame, and granulation is carried out while spraying asolution which is prepared by dissolving 3.6 g of polyethylene glycol(PEG-6000) in 896.4 ml of purified water. The granules are dried toprovide granulated powders. To the granulated powders are added 90.0 gof crospovidone and 5.4 g of magnesium stearate, which is admixed in abag to give mixed powders.

[0227] (5) Production of Orally Disintegrable Tablets

[0228] Hereinafter, the above “enteric coated granules having a core” isreferred to as “enteric coated powders”.

[0229] 200.0 g of the above enteric coated powders and 300.0 g of theabove mixed powders are tabletted using Autograph (trade name;compressing force measurement apparatus) with a punch having a bevelededge, 11 mm in diameter, at a tabletting pressure of 1.0 ton/cm² toprovide tablets each weighing 500 mg.

Reference Example 1

[0230] An alkaline cellulose comprising 24.1% of NaOH, 1.7% of Na₂CO₃,42.9% of cellulose, 31.8% of H₂O was obtained by immersing a wood pulpin 49% aqueous solution of sodium hydroxide and then by pressing it. Areactor was charged with 100 weight parts of the alkaline cellulose.Then, nitrogen gas replacement was carried out. After the replacement, 5weight parts of propylene oxide was charged in the reactor and reactedwith stirring at 40° C. for 1 hour, at 50° C. for 1 hour and at 70° C.for 1 hour to obtain 103 weight parts of a reactant.

[0231] On the other side, a kneader was charged with 2.5 weight parts ofhot water at 65° C. and 0.13 weight parts of glacial acetic acid (about40 weight % against equivalent for neutralization, initial neutralizedacid) and therein, 1 weight part of the above resulting alkalinecellulose was dispersed. Then, the temperature was set at 30° C. todissolve a part of the reactant, and 0.20 weight part of glacial aceticacid (the remainder of an equivalent for neutralization, completeneutralized acid) to obtain a processed fiber product containing a partof dissolution and a part of deposit.

[0232] The resulting product was washed with hot water at about 80° C.,drained, dried, ground by means of a high rolling impact grinder, andsifted by means of a 100 mesh sieve to obtain the powder oflow-substituted hydroxypropyl cellulose LH-33 (the content ofhydroxypropoxyl group: 5.8 weight %, the average particle diameter: 17.8μm).

Reference Example 2

[0233] Powders of low-substituted hydroxypropyl cellulose LH-23(hydroxypropoxyl group contents: 5.7 weight %, average particlediameter: 30.8 μm) were obtained in the same manner as in ReferenceExample 1.

Example 2

[0234] (1) Production of Granules Having a Core

[0235] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 300 g ofNonpareil 105 [(trade name) particle diameter: 100 to 200 μm]. With theinlet air temperature and the temperature of the loading beingcontrolled at 70° C. and about 30° C., respectively, the Nonpareil wascoated by spraying a spray liquid of the following composition preparedin advance in accordance with the tangential spray method at a sprayrate of 22 g /min., and then drying was carried out in the granulatorfor 10 minutes. The resulting granules were sieved through a #48circular sieve (300 μm) and a #100 circular sieve (150 μm) to provide2186 g of powders (150 to 300 μm) having a core. Spray liquid:Lansoprazole 927 g Magnesium carbonate 309 g Low-substitutedhydroxypropyl cellulose LH-32 154.5 g (hydroxypropoxyl group contents:8.8 wt %) (average particle diameter: 17.57 μm) Hydroxypropyl cellulose(Type SSL) 309 g Purified water 3955 g

[0236] (2) Production of Film-Undercoated Granules Having a Core

[0237] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 2040 g of theabove granules having a core. With the inlet air temperature and thetemperature of the loading being controlled at 75° C. and about 40° C.,respectively, an undercoating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 13 g /min. to provide 2145 g offilm-undercoated granules having a core. Undercoating liquid:Hydroxypropylmethylcellulose 264 g (Type 2910, viscosity: 3 centistokes)Purified water 5016 g

[0238] (3) Production of Enteric Coated Granules Having a Core

[0239] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 1710 g of theabove film-undercoated granules having a core. With the inlet airtemperature and the temperature of the loading being controlled at 70°C. and about 40° C., respectively, an enteric film coating liquid of thefollowing composition prepared in advance was sprayed in accordance withthe tangential spray method at a spray rate of 17 g /min., and dried for7 minutes, and then sieved through a #42 circular sieve (355 μm) and a#80 circular sieve (177 μm) to provide 2393 g of enteric coated powders(177 to 355 μm) having a core. Enteric film coating liquid: EudragitL30D-55 5016.4 g Eudragit NE30D 559.0 g Triethyl citrate 333.7 gGlyceryl monostearate 106.5 g Polysorbate 80 34.8 g Red iron oxide 1.8 gPurified water 2547.1 g

[0240] (4) Production of Enteric Coated and Mannitol Coated GranulesHaving a Core

[0241] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 600 g of theabove enteric coated granules having a core. With the inlet airtemperature and the temperature of the loading being controlled at 65°C. and about 32° C., respectively, an film coating liquid of thefollowing composition prepared in advance was sprayed in accordance withthe tangential spray method at a spray rate of 11 g /min., and thendried for 7 minutes to provide 617 g of enteric coated and mannitolcoated granules having a core.

[0242] The average particle diameter of the obtained granules was 334.1μm. Film coating liquid: Mannitol 33 g Purified water 297 g

[0243] (5) Production of Mannitol-Granulated Powders

[0244] A fluidized bed granulator [manufactured by Powrex Corp. (Japan),LAB-1] was charged with 800 g of mannitol [manufactured by Merck JapanCo., Ltd.], and granulation was carried out while spraying 315 g ofpurified water. The granules were dried to provide 727.3 g of granulatedpowders.

[0245] (6) Production of Mixed Powders

[0246] To 97.3 g of the above mannitol-granulated powders were added 105g of the above enteric coated and mannitol coated granules having acore, 15.0 g of low-substituted hydroxypropyl cellulose LH-33(hydroxypropoxyl group contents: 5.8 weight %, average particlediameter: 17.8 μm), 22.5 g of crystalline cellulose [CEOLUS KG-801(trade name), manufactured by Asahi Chemical Co., Ltd. (Japan)], 7.5 gof crospovidone, 1.5 g of citric acid anhydrous, 0.45 g of aspartame and0.75 g of magnesium stearate, which was admixed in a bag to give mixedpowders.

[0247] (7) Production of Orally Disintegrable Tablets

[0248] 250.0 g of the above mixed powders were tabletted using Autograph(trade name; compressing force measurement apparatus) with a punch (15R), 11 mm in diameter, at a tabletting pressure of 1.5 ton/cm², toprovide tablets each weighing 500 mg.

[0249] The hardness and oral disintegration time of each tablet thusobtained were 5.9 kg and 30 seconds, respectively.

Example 3

[0250] (1) Production of Granules Having a Core

[0251] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 900 g ofNonpareil 105 (trade name) (particle diameter of 100 to 200 μm). Withthe inlet air temperature and the temperature of the loading beingcontrolled at 75° C. and about 29° C. respectively, the Nonpareil wascoated by spraying a bulk liquid of the following composition preparedin advance in accordance with the tangential spray method at a sprayrate of 22 g /min. The spraying operation was stopped when the specifiedamount 5654.7 g of the bulk liquid had been sprayed, and then drying wascarried out in the granulator for 10 minutes. The resulting granuleswere sieved through a #60 circular sieve (250 μm) and a #100 circularsieve (150 μm) to provide 2424 g of granules having a core. Bulk liquid:Lansoprazole 1080 g Magnesium carbonate 360 g Low-substitutedhydroxypropyl cellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8weight %) Hydroxypropyl cellulose (Type SSL) 360 g Purified water 4608 g

[0252] (2) Production of Film-Undercoated Granules Having a Core

[0253] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type2)] was charged with 2337.5 g of theabove granules having a core. With the inlet air temperature and thetemperature of the loading being controlled at 80° C. and about 41° C.,respectively, an undercoating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 18 g /min. The spraying operation was stoppedwhen the specified amount 6050 g of the undercoating liquid had beensprayed, and then drying was carried out in the granulator for 10minutes to provide 2551 g of film-undercoated granules having a core.Undercoating liquid: Hydroxypropyl methylcellulose 332.5 g (Type 2910,viscosity: 3 centistokes) Low-substituted hydroxypropyl cellulose LH-3217.5 g (hydroxypropoxyl group contents: 8.8 weight %) (average particlediameter: 17.57 μm) Purified water 6650 g

[0254] (3) Production of Enteric Coated Granules Having a Core

[0255] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 570 g of theabove film-undercoated granules having a core. With the inlet airtemperature and the temperature of the loading being controlled at 75°C. and about 40° C., respectively, an enteric film coating liquid of thefollowing composition prepared in advance was sprayed in accordance withthe tangential spray method at a spray rate of 18 g /min. The sprayingoperation was stopped when the specified amount 2646 g of the entericfilm coating liquid had been sprayed, and then drying was carried out inthe granulator for 8 minutes. The coated powders were sieved through a#42 circular sieve (355 μm) and a #70 circular sieve (212 μm) to provide1116 g of enteric coated granules having a core.

[0256] The average particle diameter of the obtained granules was 326.9μm. Enteric film coating liquid: Eudragit L30D-55 1911 g Eudragit NE30D212.9 g Triethyl citrate 127.1 g Glyceryl monostearate 40.6 gPolysorbate 80 13.3 g Red iron oxide 0.8 g Purified water 970.3 g

[0257] (4) Production of Mixed Powders

[0258] To 200 g of the above enteric coated granules having a core wereadded 189.7 g of mannitol, 30.0 g of low-substituted hydroxypropylcellulose LH-23 (hydroxypropoxyl group contents: 5.8 weight %, averageparticle diameter: 17.8 μm), 60.0 g of crystalline cellulose [CEOLUSKG-801 (trade name), manufactured by Asahi Chemical Co., Ltd. (Japan)],15.0 g of crospovidone, 2.8 g of citric acid anhydrous and 25 g ofmagnesium stearate, which was admixed in a bag to give mixed powders.

[0259] (5) Production of Orally Disintegrable Tablets

[0260] 250.0 g of the above mixed powders were tabletted using Autograph(trade name; compressing force measurement apparatus) with a punch (15R), 11 mm in diameter, at a tabletting pressure of 1.5 ton/cm², toprovide tablets each weighing 500 mg.

[0261] The hardness and oral disintegration time of each tablet thusobtained were 4.2 kg and 24 seconds, respectively.

Example 4

[0262] (1) Production of Granules Having a Core

[0263] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 900 g ofNonpareil 105 (trade name) (particle diameter of 100 to 200 μm).

[0264] With the inlet air temperature and the temperature of the loadingbeing controlled at 75° C. and about 32° C. respectively, the Nonpareilwas coated by spraying a bulk liquid of the following compositionprepared in advance in accordance with the tangential spray method at aspray rate of 20 g /min. The spraying operation was stopped when thespecified amount 5654.7 g of the bulk liquid had been sprayed, and thendrying was carried out in the granulator for 10 minutes. The resultinggranules were sieved through a #48 circular sieve (300 μm) and a #100circular sieve (150 μm) to provide 2280 g of granules having a core.Bulk liquid: Lansoprazole 1080 g Magnesium carbonate  360 gLow-substituted hydroxypropyl cellulose LH-32  180 g (hydroxypropoxylgroup contents: 8.8 weight %) Hydroxypropyl cellulose (Type SSL)  360 gPurified water 4608 g

[0265] (2) Production of Film-Undercoated Granules Having a Core

[0266] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 1020 g of theabove granules having a core. With the inlet air temperature and thetemperature of the loading being controlled at 85° C. and about 40° C.,respectively, an undercoating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 15 g /min. The spraying operation was stoppedwhen the specified amount 1980 g of the undercoating liquid had beensprayed, and then drying was carried out in the granulator for 10minutes to provide 1330.5 g of film-undercoated granules having a core.Undercoating liquid: Hydroxypropylmethylcellulose  120 g (Type 2910,viscosity: 3 centistokes) Titanium oxide (TiO₂)  240 g Sterilized Talc(trade name)  240 g [produced by Matsumura Sangyo Co. Ltd. (Japan)]Magnesium carbonate  120 g Purified water 2880 g

[0267] (3) Production of Enteric Coated Granules Having a Core

[0268] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 460 g of theabove film-undercoated granules having a core. With the inlet airtemperature and the temperature of the loading being controlled at 80°C. and about 41° C., respectively, an enteric film coating liquid of thefollowing composition prepared in advance was sprayed in accordance withthe tangential spray method at a spray rate of 13 g /min. The sprayingoperation was stopped when the specified amount 2205 g of the entericfilm coating liquid had been sprayed. Enteric film coating liquid:Eudragit L30D-55 2290 g Eudragit NE30D  253 g Triethyl citrate  153 gGlyceryl monostearate  20 g Polysorbate 80   8 g Titanium oxide (TiO₂) 53 g Sterilized Talc H (trade name)  53 g [produced by Matsumura SangyoCo. Ltd. (Japan)] Purified water 2420 g

[0269] (4) Production of Enteric Coated and Mannitol Coated GranulesHaving a Core

[0270] Following (3), with the inlet air temperature and the temperatureof the loading being controlled at 80° C. and about 35° C.,respectively, an film coating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 16 g /min. using a centrifugal fluidizedcoating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type2)]. The spraying operation was stopped when the specified amount 824 gof the film coating liquid had been sprayed, and then drying was carriedout in the granulator for 10 minutes. The resulting granules were sievedthrough a #42 circular sieve (355 μm) and a #60 circular sieve (250 μm)to provide 806 g of enteric coated and mannitol coated granules having acore.

[0271] The average particle diameter of the obtained granules was 326.6μm. Film coating liquid: Mannitol  320 g Purified water 2880 g

[0272] (5) Production of Mixed Powders

[0273] To 120 g of the above enteric coated and mannitol coated granuleshaving a core were added 87.75 g of mannitol, 8.5 g of low-substitutedhydroxypropyl cellulose LH-23 (hydroxypropoxyl group contents: 5.8weight %), 4.5 g of low-substituted hydroxypropyl cellulose LH-33(hydroxypropoxyl group contents: 5.8 weight %), 19.5 g of crystallinecellulose [CEOLUS KG-801 (trade name), manufactured by Asahi ChemicalCo., Ltd. (Japan)], 6.5 g of crospovidone, 1.3 g of citric acidanhydrous, 1.3 g of aspartame and 0.65 g of magnesium stearate, whichwas admixed in a bag to give mixed powders.

[0274] (6) Production of Orally Disintegrable Tablets

[0275] 250.0 g of the above mixed powders were tabletted using Autograph(trade name; compressing force measurement apparatus) with a punch (15R), 11 mm in diameter, at a tabletting pressure of 1.5 ton/cm², toprovide tablets each weighing 500 mg.

[0276] The hardness and oral disintegration time of each tablet thusobtained were 3.9 kg and 20.5 seconds, respectively.

[0277] The remaining ratio of the obtained tablet after acid-resistancetest was 97%.

Example 5

[0278] (1) Production of Granules Having a Core

[0279] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 900 g ofNonpareil 105 (trade name) (particle diameter of 100 to 200 μm). Withthe inlet air temperature and the temperature of the loading beingcontrolled at 65° C. and about 30° C. respectively, the Nonpareil wascoated by spraying a bulk liquid of the following composition preparedin advance in accordance with the tangential spray method at a sprayrate of 22 g /min. The spraying operation was stopped when the specifiedamount 5661 g of the bulk liquid had been sprayed, and then drying wascarried out in the granulator for 8 minutes. The resulting granules weresieved through a #42 circular sieve (350 μm) and a #100 circular sieve(150 μm) to provide 2074 g of granules having a core. Bulk liquid:Lansoprazole 1080 g Magnesium carbonate  360 g Low-substitutedhydroxypropyl cellulose LH-32  180 g (hydroxypropoxyl group contents:8.8 weight %) Hydroxypropyl cellulose (Type SSL)  360 g Purified water4680 g

[0280] (2) Production of Film-Undercoated Granules Having a Core

[0281] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 2074 g of theabove granules having a core. With the inlet air temperature and thetemperature of the loading being controlled at 78° C. and about 40° C.,respectively, an undercoating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 22 g /min. The spraying operation was stoppedwhen the specified amount 1980 g of the undercoating liquid had beensprayed, and then drying was carried out in the granulator for 9minutes. The resulting granules were sieved through a #42 circular sieve(350 μm) and a #100 circular sieve (150 μm) to provide 2555 g offilm-undercoated granules having a core. Undercoating liquid:Hydroxypropylmethylcellulose  252 g (Type 2910, viscosity: 3centistokes) Titanium oxide (TiO₂)  108 g Sterilized Talc (trade name) 108 g [produced by Matsumura Sangyo Co. Ltd. (Japan)] Low-substitutedhydroxypropyl cellulose LH-32  180 g (hydroxypropoxyl group contents:8.8 weight %) Mannitol  252 g Purified water 3600 g

[0282] (3) Production of Enteric Coated Granules Having a Core

[0283] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 1320 g of theabove film-undercoated granules having a core. With the inlet airtemperature and the temperature of the loading being controlled at 80°C. and about 42° C., respectively, an enteric film coating liquid (A) ofthe following composition prepared in advance was sprayed in accordancewith the tangential spray method at a spray rate of 22 g /min. Thespecified amount 1638 g of the enteric film coating liquid had beensprayed. Enteric film coating liquid (A): Eudragit L30D-55 1219.2 gEudragit NE30D  134.4 g Polyethylene glycol 6000  40.8 g Glycerylmonostearate  24.0 g Polysorbate 80   7.2 g Ferric oxide  0.24 g Ferricoxide (yellow)  0.24 g Citric acid anhydrous  0.48 g Purified water  1693 g

[0284] Following this, with the inlet air temperature and thetemperature of the loading being controlled at 76° C. and about 42° C.,respectively, an enteric film coating liquid (B) of the followingcomposition prepared in advance was sprayed in accordance with thetangential spray method at a spray rate of 22 g /min. The specifiedamount 6552 g of the enteric film coating liquid had been sprayed.Enteric film coating liquid (B): Eudragit L30D-55  4032 g Eudragit NE30D447.8 g Triethyl citrate 269.3 g Glyceryl monostearate  86.4 gPolysorbate 80  25.9 g Ferric oxide  0.86 g Ferric oxide (yellow)  0.86g Citric acid anhydrous  0.72 g Purified water  2624 g

[0285] Following this, with the inlet air temperature and thetemperature of the loading being controlled at 80° C. and about 42° C.,respectively, an enteric film coating liquid (A) of the above mentionedcomposition prepared in advance was sprayed in accordance with thetangential spray method at a spray rate of 22 g /min. The specifiedamount 819 g of the enteric film coating liquid had been sprayed.

[0286] (4) Production of Enteric Coated and Mannitol Coated GranulesHaving a Core

[0287] Following (3), with the inlet air temperature and the temperatureof the loading being controlled at 85° C. and about 35° C.,respectively, an film coating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 22 g /min. using a centrifugal fluidizedcoating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type2)]. The spraying operation was stopped when the specified amount 882 gof the film coating liquid had been sprayed, and then drying was carriedout in the granulator for 10 minutes. The resulting granules were sievedthrough a #35 circular sieve (420 μm) and a #60 circular sieve (250 μm)to provide 1964 g of enteric coated and mannitol coated granules havinga core.

[0288] The average particle diameter of the obtained granules was 333.7μm. Film coating liquid: Mannitol  180 g Purified water 1080 g

[0289] (5) Production of Mixed Powders

[0290] To 270 g of the above enteric coated and mannitol coated granuleshaving a core were added 204.0 g of mannitol, 30 g of low-substitutedhydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8weight %), 30 g of crystalline cellulose [CEOLUS KG-801 (trade name),manufactured by Asahi Chemical Co., Ltd. (Japan)], 15 g of crospovidone,3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magnesiumstearate and 3 g of flavor [STRAWBERRY DURAROME (trade name),manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed ina bag to give mixed powders.

[0291] (6) Production of Orally Disintegrable Tablets

[0292] 570 g of the above mixed powders were tabletted using Autograph(trade name; compressing force measurement apparatus) with a punchhaving a beveled edge, 13 mm in diameter, at a tabletting pressure of1.5 ton/cm², to provide tablets each weighing 570 mg.

[0293] The hardness and oral disintegration time of each tablet thusobtained were 2.6 kg and 20 seconds, respectively.

[0294] The acid-resistance of the obtained tablet was 3.5%.

Example 6

[0295] (1) Production of Granules Having a Core

[0296] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 750 g ofNonpareil 105 (trade name) (particle diameter of 100 to 200 μm). Withthe inlet air temperature and the temperature of the loading beingcontrolled at 65° C. and about 30° C. respectively, the Nonpareil wascoated by spraying a bulk liquid of the following composition preparedin advance in accordance with the tangential spray method at a sprayrate of 22 g /min. The spraying operation was stopped when the specifiedamount 4717.5 g of the bulk liquid had been sprayed, and then drying wascarried out in the granulator for 8 minutes. The resulting granules weresieved through a #42 circular sieve (350 μm) and a #100 circular sieve(150 μm) to provide 1811 g of granules having a core. Bulk liquid:Lansoprazole  900 g Magnesium carbonate  300 g Low-substitutedhydroxypropyl cellulose LH-32  150 g (hydroxypropoxyl group contents:8.8 weight %) Hydroxypropyl cellulose (Type SSL)  300 g Purified water3900 g

[0297] (2) Production of Film-undercoated Granules Having a Core

[0298] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 1811 g of theabove granules having a core. With the inlet air temperature and thetemperature of the loading being controlled at 78° C. and about 38° C.,respectively, an undercoating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 22 g /min. The spraying operation was stoppedwhen the specified amount 5274 g of the undercoating liquid had beensprayed, and then drying was carried out in the granulator for 9minutes. The resulting granules were sieved through a #42 circular sieve(350 μm) and a #100 circular sieve (150 μm) to provide 2628 g offilm-undercoated granules having a core. Undercoating liquidHydroxypropylmethylcellulose 378 g (Type 2910, viscosity: 3 centistokes)Titanium oxide (TiO₂) 162 g Sterilized Talc (trade name) 162 g [producedby Matsumura Sangyo Co. Ltd. (Japan)] Low-substituted hydroxypropylcellulose LH-32 270 g (hydroxypropoxyl group contents: 8.8 weight %)Mannitol 378 g Purified water 5400 g

[0299] (3) Production of Enteric Coated Granules Having a Core

[0300] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 1560 g of theabove film-undercoated granules having a core. With the inlet airtemperature and the temperature of the loading being controlled at 70°C. and about 40° C., respectively, an enteric film coating liquid (A) ofthe following composition prepared in advance was sprayed in accordancewith the tangential spray method at a spray rate of 19 g /min. Thespecified amount 6048 g of the enteric film coating liquid had beensprayed. Enteric film coating liquid (A) Eudragit L30D-55 4032 gEudragit NE30D 447.8 g Triethyl citrate 269.3 g Glyceryl monostearate86.4 g Polysorbate 80 25.9 g Ferric oxide 0.86 g Ferric oxide (yellow)0.86 g Citric acid anhydrous 0.72 g Purified water 2624 g

[0301] Following this, with the inlet air temperature and thetemperature of the loading being controlled at 72° C. and about 42° C.,respectively, an enteric film coating liquid (B) of the followingcomposition prepared in advance was sprayed in accordance with thetangential spray method at a spray rate of 19 g /min. The specifiedamount 819 g of the enteric film coating liquid had been sprayed.Enteric film coating liquid (B) Eudragit L30D-55 609.6 g Eudragit NE30D68.0 g Polyethylene glycol 6000 20.4 g Glyceryl monostearate 12.0 gPolysorbate 80 3.6 g Ferric oxide 0.12 g Ferric oxide (yellow) 0.12 gCitric acid anhydrous 0.24 g Purified water 846.7 g

[0302] (4) Production of Enteric Coated and Mannitol Coated GranulesHaving a Core

[0303] Following (3), while the inlet air temperature and thetemperature of the loading being controlled at 65° C. and about 38° C.,respectively, an film coating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 19 g /min. using a centrifugal fluidizedcoating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type2)]. The spraying operation was stopped when the specified amount 882 gof the film coating liquid had been sprayed, and then drying was carriedout in the granulator for 17 minutes. The resulting granules were sievedthrough a #35 circular sieve (420 μm) and a #60 circular sieve (250 μm)to provide 2825 g of enteric coated and mannitol coated granules havinga core.

[0304] The average particle diameter of the obtained granules was 330.5μm. Film coating liquid Mannitol 180 g Purified water 1080 g

[0305] (5) Production of Mixed Powders

[0306] To 270 g of the above enteric coated and mannitol coated granuleshaving a core were added 204.0 g of mannitol, 30 g of low-substitutedhydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8weight %), 30 g of crystalline cellulose [CEOLUS KG-801 (trade name),manufactured by Asahi Chemical Co., Ltd. (Japan)], 15 g of crospovidone,3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magnesiumstearate and 3 g of flavor [STRAWBERRY DURAROME (trade name),manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed ina bag to give mixed powders.

[0307] (6) Production of Orally Disintegrable Tablets

[0308] 570 g of the above mixed powders were tabletted using Autograph(trade name; compressing force measurement apparatus) with a punchhaving a beveled edge, 13 mm in diameter, at a tabletting pressure of1.5 ton/cm², to provide tablets each weighing 570 mg.

[0309] The hardness and oral disintegration time of each tablet thusobtained were 3.1 kg and 22 seconds, respectively.

[0310] The acid-resistance of the obtained tablet was 2.5%.

Example 7

[0311] (1) Production of Granules Having a Core

[0312] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2) ] was charged with 750 g ofNonpareil 105 (trade name) (particle diameter of 100 to 200 μm). Withthe inlet air temperature and the temperature of the loading beingcontrolled at 75° C. and about 30° C. respectively, the Nonpareil wascoated by spraying a bulk liquid of the following composition preparedin advance in accordance with the tangential spray method at a sprayrate of 20 g /min. The spraying operation was stopped when the specifiedamount 4717.5 g of the bulk liquid had been sprayed, and then drying wascarried out in the granulator for 10 minutes to provide 1842 g ofgranules having a core. Bulk liquid Lansoprazole 900 g Magnesiumcarbonate 300 g Low-substituted hydroxypropyl cellulose LH-32 150 g(hydroxypropoxyl group contents: 8.8 weight %) Hydroxypropyl cellulose(Type SSL) 300 g Purified water 3900 g

[0313] (2) Production of Film-Undercoated Granules Having a Core

[0314] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 1842 g of theabove granules having a core. With the inlet air temperature and thetemperature of the loading being controlled at 74° C. and about 38° C.,respectively, an undercoating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 19 g /min. The spraying operation was stoppedwhen the specified amount 5365 g of the undercoating liquid had beensprayed, and then drying was carried out in the granulator for 9minutes. The resulting granules were sieved through a #42 circular sieve(350 μm) and a #100 circular sieve (150 μm) to provide 2770 g offilm-undercoated granules having a core. Undercoating liquidHydroxypropylmethylcellulose 378 g (Type 2910, viscosity: 3 centistokes)Titanium oxide (TiO₂) 162 g Sterilized Talc (trade name) 162 g [producedby Matsumura Sangyo Co. Ltd. (Japan)] Low-substituted hydroxypropylcellulose LH-32 270 g (hydroxypropoxyl group contents: 8.8 weight %)Mannitol 378 g Purified water 5400 g

[0315] (3) Production of Enteric Coated Granules Having a Core

[0316] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 1300 g of theabove film-undercoated granules having a core. With the inlet airtemperature and the temperature of the loading being controlled at 78°C. and about 39° C., respectively, an enteric film coating liquid (A) ofthe following composition prepared in advance was sprayed in accordancewith the tangential spray method at a spray rate of 21 g /min. Thespraying operation was stopped when the specified amount 5040 g of theenteric film coating liquid had been sprayed, and then drying wascarried out in the granulator for 16 minutes. The resulting granuleswere sieved through a #35 circular sieve (420 μm) and a #60 circularsieve (250 μm) to provide 2453 g of enteric coated granules having acore. Enteric film coating liquid (A) Eudragit L30D-55 4032 g EudragitNE30D 447.8 g Triethyl citrate 269.3 g Glyceryl monostearate 86.4 gPolysorbate 80 25.9 g Ferric oxide 0.86 g Ferric oxide (yellow) 0.86 gCitric acid anhydrous 0.72 g Purified water 2624 g

[0317] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 1000 g of theabove enteric coated granules having a core. With the inlet airtemperature and the temperature of the loading being controlled at 80°C. and about 38° C., respectively, an enteric film coating liquid (B) ofthe following composition prepared in advance was sprayed in accordancewith the tangential spray method at a spray rate of 19 g /min. Thespecified amount 273 g of the enteric film coating liquid had beensprayed. Enteric film coating liquid (B) Eudragit L30D-55 610.4 gEudragit NE30D 68.0 g Polyethylene glycol 6000 20.4 g Glycerylmonostearate 12.0 g Polysorbate 80 3.6 g Ferric oxide 0.12 g Ferricoxide (yellow) 0.12 g Citric acid anhydrous 0.24 g Purified water 845.12g

[0318] (4) Production of Enteric Coated and Mannitol Coated GranulesHaving a Core

[0319] Following (3), while the inlet air temperature and thetemperature of the loading being controlled at 75° C. and about 35° C.,respectively, an film coating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 20 g /min. using a centrifugal fluidizedcoating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type2)]. The spraying operation was stopped when the specified amount 294 gof the film coating liquid had been sprayed, and then drying was carriedout in the granulator for 10 minutes. The resulting granules were sievedthrough a #35 circular sieve (420 μm) and a #60 circular sieve (250 μm)to provide 1061 g of enteric coated and mannitol coated granules havinga core.

[0320] The average particle diameter of the obtained granules was 307.1μm. Film coating liquid Mannitol 120 g Purified water 720 g

[0321] (5) Production of Mixed Powders

[0322] To 270 g of the above enteric coated and mannitol coated granuleshaving a core were added 207 g of mannitol, 30 g of low-substitutedhydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8weight %), 30 g of crystalline cellulose [CEOLUS KG-801 (trade name),manufactured by Asahi Chemical Co., Ltd. (Japan)], 15 g of crospovidone,3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magnesiumstearate and 3 g of flavor [STRAWBERRY DURAROME (trade name),manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed ina bag to give mixed powders.

[0323] (6) Production of Orally Disintegrable Tablets

[0324] 570 g of the above mixed powders were tabletted using Autograph(trade name; compressing force measurement apparatus) with a punchhaving a beveled edge, 13 mm in diameter, at a tabletting pressure of1.5 ton/cm², to provide tablets each weighing 570 mg.

[0325] The hardness and oral disintegration time of each tablet thusobtained were 3.2 kg and 24 seconds, respectively.

Example 8

[0326] (1) Production of Granules Having a Core

[0327] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 900 g ofNonpareil 105T (trade name) (particle diameter of 100 to 200 μm). Withthe inlet air temperature and the temperature of the loading beingcontrolled at 71 to 78° C. and about 31 ° C. respectively, the Nonpareilwas coated by spraying a bulk liquid of the following compositionprepared in advance in accordance with the tangential spray method at aspray rate of 21 g /min. The spraying operation was stopped when thespecified amount 5550 g of the bulk liquid had been sprayed, and thendrying was carried out in the granulator for 21 minutes. The resultinggranules were sieved through a #42 circular sieve (350 μm) and a #100circular sieve (150 μm) to provide 1723 g of granules having a core.Bulk liquid Lansoprazole 1080 g Magnesium carbonate 360 gLow-substituted hydroxypropyl cellulose LH-32 180 g (hydroxypropoxylgroup contents: 8.8 weight %) Hydroxypropyl cellulose (Type SSL) 360 gPurified water 4680 g

[0328] (2) Production of Film-Undercoated Granules Having a Core

[0329] A centrifugal fluidized coating granulator [ manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 2074 g of theabove granules having a core. With the inlet air temperature and thetemperature of the loading being controlled at 77° C. and about 41° C.,respectively, an undercoating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 21 g /min. The spraying operation was stoppedwhen the specified amount 2787 g of the undercoating liquid had beensprayed, and then drying was carried out in the granulator for 13minutes. The resulting granules were sieved through a #42 circular sieve(350 μm) and a #100 circular sieve (150 μm) to provide 1958 g offilm-undercoated granules having a core. Undercoating liquid:Hydroxypropylmethylcellulose 252 g (Type 2910, viscosity: 3 centistokes)Titanium oxide (TiO₂) 108 g Sterilized Talc (trade name) 108 g [producedby Matsumura Sangyo Co. Ltd. (Japan)] Low-substituted hydroxypropylcellulose LH-32 180 g (hydroxypropoxyl group contents: 8.8 weight %)Mannitol 252 g Purified water 3600 g

[0330] (3) Production of Enteric Coated Granules Having a Core

[0331] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 1100 g of theabove film-undercoated granules having a core. With the inlet airtemperature and the temperature of the loading being controlled at 80°C. and about 41° C., respectively, an enteric film coating liquid (A) ofthe following composition prepared in advance was sprayed in accordancewith the tangential spray method at a spray rate of 22 g /min. Thespecified amount 1365 g of the enteric film coating liquid had beensprayed. Enteric film coating liquid (A): Eudragit L30D-55 1017.3 gEudragit NE30D 113.3 g Polyethylene glycol 6000 34.0 g Glycerylmonostearate 20.0 g Polysorbate 80 6.0 g Ferric oxide 0.2 g Ferric oxide(yellow) 0.2 g Citric acid anhydrous 0.4 g Purified water 1410.8 g

[0332] Following this, with the inlet air temperature and thetemperature of the loading being controlled at 76° C. and about 41° C.,respectively, an enteric film coating liquid (B) of the followingcomposition prepared in advance was sprayed in accordance with thetangential spray method at a spray rate of 22 g /min. The specifiedamount 5040 g of the enteric film coating liquid had been sprayed.Enteric film coating liquid (B): Eudragit L30D-55 3360 g Eudragit NE30D373.2 g Triethyl citrate 224.4 g Glyceryl monostearate 72.0 gPolysorbate 80 21.6 g Ferric oxide 0.72 g Ferric oxide (yellow) 0.72 gCitric acid anhydrous 0.6 g Purified water 1706.8 g

[0333] Following this, with the inlet air temperature and thetemperature of the loading being controlled at 80° C. and about 42° C.,respectively, an enteric film coating liquid (A) of the above mentionedcomposition prepared in advance was sprayed in accordance with thetangential spray method at a spray rate of 21 g /min. The specifiedamount 682.5 g of the enteric film coating liquid had been sprayed.

[0334] (4) Production of Enteric Coated and Mannitol Coated GranulesHaving a Core

[0335] Following (3), with the inlet air temperature and the temperatureof the loading being controlled at 80° C. and about 36° C.,respectively, an film coating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 22 g /min. using a centrifugal fluidizedcoating granulator [manufactured by Powrex Corp. (Japan), MP-10 (Type2)]. The spraying operation was stopped when the specified amount 735 gof the film coating liquid had been sprayed, and then drying was carriedout in the granulator for 10 minutes. The resulting granules were sievedthrough a #35 circular sieve (420 μm) and a #60 circular sieve (250 μm)to provide 2319.5 g of enteric coated and mannitol coated granuleshaving a core.

[0336] The average particle diameter of the obtained granules was 392.7μm. Film coating liquid: Mannitol 100 g Purified water 600 g

[0337] (5) Production of Mixed Powders

[0338] To 270 g of the above enteric coated and mannitol coated granuleshaving a core were added 204.0 g of mannitol, 30 g of low-substitutedhydroxypropyl cellulose LH-33 (hydroxypropoxyl group contents: 5.8weight %), 30 g of crystalline cellulose [CEOLUS KG-801 (trade name),manufactured by Asahi Chemical Co., Ltd. (Japan)], 15 g of crospovidone,3 g of citric acid anhydrous, 9 g of aspartame, 6 g of magnesiumstearate and 3 g of flavor [STRAWBERRY DURAROME (trade name),manufactured by Nihon Filmenich Co., Ltd. (Japan)], which was admixed ina bag to give mixed powders.

[0339] (6) Production of Orally Disintegrable Tablets

[0340] 570 g of the above mixed powders were tabletted using Autograph(trade name; compressing force measurement apparatus) with a punchhaving a beveled edge, 12 mm in diameter, at a tabletting pressure of1.5 ton/cm², to provide tablets each weighing 570 mg.

[0341] The hardness and oral disintegration time of each tablet thusobtained were 3.7 kg and 35 seconds, respectively.

[0342] The acid-resistance of the obtained tablet was 3.4%.

Example 9

[0343] (1) Production of Granules Having a Core

[0344] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 300 g ofNonpareil 105 (70-140) (particle diameter of 100 to 200 μm). With theinlet air temperature and the temperature of the loading beingcontrolled at 85° C. and about 28° C. respectively, the Nonpareil wascoated by spraying a bulk liquid of the following composition preparedin advance in accordance with the tangential spray method at a sprayrate of 20 g /min. The spraying operation was stopped when the specifiedamount of the bulk liquid had been sprayed, and then drying was carriedout in the granulator for 7 minutes. The resulting granules were sievedthrough a #48 circular sieve (300 μm) and a #100 circular sieve (150 μm)to provide 757 g of granules having a core. Bulk liquid: Lansoprazole300 g Magnesium carbonate 100 g L-HPC 50 g HPC (Type SSL) 100 g Water1650 g

[0345] (2) Production of Film-Undercoated Granules Having a Core

[0346] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 680 g of theabove granules having a core. With the inlet air temperature and thetemperature of the loading being controlled at 70° C. and about 36° C.,respectively, an undercoating liquid of the following compositionprepared in advance was sprayed in accordance with the tangential spraymethod at a spray rate of 10 g /min. to provide 672 g offilm-undercoated granules having a core. Undercoating liquid: HPMC 32 g(Type 2910, viscosity: 3 centistokes) Talc 8 g Water 760 g

[0347] (3) Production of Enteric Coated Granules Having a Core

[0348] A centrifugal fluidized coating granulator [manufactured byPowrex Corp. (Japan), MP-10 (Type 2)] was charged with 450 g of theabove film-undercoated granules having a core. With the inlet airtemperature and the temperature of the loading being controlled at 65°C. and about 36° C., respectively, an enteric film coating liquid of thefollowing composition prepared in advance was sprayed in accordance withthe tangential spray method at a spray rate of 17 g /min. The coatedpowders were dried in vacuum at 40° C. for 16 hours, and sieved througha #42 circular sieve (355 μm) and a #80 circular sieve (177 μm) toprovide 950 g of enteric coated granules having a core.

[0349] The average particle diameter of the obtained granules was 285.4μm. Enteric film coating liquid: Eudragit L30D-55 1078.3 g EudragitNE30D  138.5 g Triethyl citrate  46.0 g Glyceryl monostearate  16.5 gTalc  16.0 g Polysorbate 80   9.0 g Iron oxide   0.5 g Water 2038.5 gSieve weight ratio #18 (850 μm) on 0% #30 (500 μm) on 0% #200 (75 μm) on100%  #200 (75 μm) pass 0%

[0350] (4) Production of Granulated Powders

[0351] A fluidized bed granulator [manufactured by Powrex Corp. (Japan),LAB-1] was charged with 1321.2 g of erythritol [manufactured by NikkenChemical Co., Ltd. (Japan)], 360.0 g of low-substituted hydroxypropylcellulose LH-32 [hydroxypropoxyl group contents of 8.8%, manufactured byShin-Etsu Chemical Co., Ltd. (Japan)], 18.0 g of citric acid anhydrous,and 1.8 g of aspartame, and granulation was carried out while spraying asolution which was prepared by dissolving 3.6 g of polyethylene glycol(PEG-6000) in 896.4 ml of purified water. The granules were dried toprovide granulated powders. To the granulated powders were added 90.0 gof crospovidone and 5.4 g of magnesium stearate, which was admixed in abag to give mixed powders.

[0352] (5) Production of Orally Disintegrable Tablets

[0353] 200.0 g of the above enteric coated granules having a core and300.0 g of the above mixed powders were tabletted using Autograph (tradename; compressing force measurement apparatus) with a punch having abeveled edge, 11 mm in diameter, at a tabletting pressure of 1.0ton/cm², to provide tablets each weighing 500 mg.

[0354] The hardness, the oral disintegration time and remaining ratioafter acid-resistance test of each tablet thus obtained were 4.2 kg, 27seconds and 96.3%, respectively.

[0355] Industrial Applicability

[0356] The orally disintegrable tablet of the present invention hassuperior disintegrability or dissolution so that it can be used fortreatment or prevention of various diseases, as an orally disintegrabletablet capable of being administered to the aged or children and easilyadministered without water. Also, because the orally disintegrabletablet of the present invention contains fine granules having theaverage particle diameter and an enteric coating layer such that it willnot impart roughness in mouth, it can be administered easily withoutdiscomfort at the administration and has superior acid-resistance.

[0357] Further, because the orally disintegrable tablet of the presentinvention has a suitable strength such that it will not be substantiallydamaged through production processes or circulation processes, it issuperior in stability for long-term storage and easy of use at theadministration.

[0358] Further, because the fine granule of the present invention ischaracterized in that it stably retains the acid-labile physiologicallyactive substance, contains the physiologically active substance in highcontent, be small and has superior stability, it can be used forproducing various compact pharmaceutical preparations such as tablets,capsules, suspensions and so forth. Such preparations are easy of use atthe administration. In addition, the fine granule of the presentinvention has superior acid-resistance after compression.

1. An orally disintegrable tablet which comprises (i) fine granuleshaving an average particle diameter of 400 μm or less, which finegranules comprise a composition coated by an enteric coating layer, saidcomposition having 10 weight % or more of an acid-labile physiologicallyactive substance and (ii) an additive.
 2. An orally disintegrable tabletof claim 1, wherein the average particle diameter of the fine granulesis 300 to 400 μm.
 3. An orally disintegrable tablet of claim 1, whereinthe fine granules further comprise a basic inorganic salt.
 4. An orallydisintegrable tablet of claim 1, wherein the additive comprises awater-soluble sugar alcohol.
 5. An orally disintegrable tablet of claim1, wherein the composition coated by an enteric coating layer is furthercoated by a coating layer which comprises a water-soluble sugar alcohol.6. An orally disintegrable tablet of claim 4, wherein the additivecomprises (i) crystalline cellulose and/or (ii) low-substitutedhydroxypropyl cellulose.
 7. An orally disintegrable tablet of claim 1,wherein the particle diameter of the fine granules is practically 425 μmor less.
 8. An orally disintegrable tablet of claim 1, wherein theparticle diameter of the fine granules is practically 400 μm or less. 9.An orally disintegrable tablet of claim 1, wherein the acid-labilephysiologically active substance is a benzimidazole compound or a saltthereof.
 10. An orally disintegrable tablet of claim 9, wherein thebenzimidazole compound is lansoprazole.
 11. An orally disintegrabletablet of claim 3, wherein the basic inorganic salt is a salt ofmagnesium and/or a salt of calcium.
 12. An orally disintegrable tabletof claim 1, wherein the composition comprises a core being coated by abenzimidazole compound and a basic inorganic salt, said core comprisingcrystalline cellulose and lactose.
 13. An orally disintegrable tablet ofclaim 12, wherein the core comprises 50 weight % or more of lactose. 14.An orally disintegrable tablet of claim 12, wherein the core comprises40 to 50 weight % of crystalline cellulose and 50 to 60 weight % oflactose.
 15. An orally disintegrable tablet of claim 1, wherein thecomposition comprises 20 weight % or more of an acid-labilephysiologically active substance.
 16. An orally disintegrable tablet ofclaim 1, wherein the composition comprises 20 to 50 weight % of anacid-labile physiologically active substance.
 17. An orallydisintegrable tablet of claim 1, wherein the fine granules are producedby fluidized-bed granulation method.
 18. An orally disintegrable tabletof claim 1, wherein the enteric coating layer comprises an aqueousenteric polymer agent.
 19. An orally disintegrable tablet of claim 18,wherein the aqueous enteric polymer agent is a methacrylate copolymer.20. An orally disintegrable tablet of claim 18, wherein the entericcoating layer further comprises a sustained-release agent.
 21. An orallydisintegrable tablet of claim 20, wherein the sustained-release agent isa methacrylate copolymer.
 22. An orally disintegrable tablet of claim20, wherein the sustained-release agent is in an amount of 5 to 15weight % relative to 100 weight % of the aqueous enteric polymer agent.23. An orally disintegrable tablet of claim 4, wherein the water-solublesugar alcohol is erythritol.
 24. An orally disintegrable tablet of claim4, wherein the water-soluble sugar alcohol is mannitol.
 25. An orallydisintegrable tablet of claim 5, wherein the water-soluble sugar alcoholis in an amount of 5 to 97 weight % relative to 100 weight % of theorally disintegrable tablet apart from the fine granules.
 26. An orallydisintegrable tablet of claim 4, wherein the crystalline cellulose is inan amount of 3 to 50 weight % relative to 100 weight % of the tabletapart from the fine granule.
 27. An orally disintegrable tablet of claim6, wherein the content of hydroxypropoxyl group in the low-substitutedhydroxypropyl cellulose is 7.0 to 9.9 weight %.
 28. An orallydisintegrable tablet of claim 6, wherein the content of hydroxypropoxylgroup in the low-substituted hydroxypropyl cellulose is 5.0 to 7.0weight %.
 29. An orally disintegrable tablet of claim 1, which furthercomprises crospovidone.
 30. An orally disintegrable tablet of claim 1,wherein the oral disintegration time is one minute or less.
 31. Anorally disintegrable tablet of claim 1, which comprises no lubricantinside the tablet.
 32. Fine granules having an average particle diameterof 400 μm or less, which comprise a composition coated by an entericcoating layer, said composition having (i) 25 weight % or more of anacid-labile physiologically active substance and (ii) a basic inorganicsalt.
 33. Fine granules of claim 32, wherein the average particlediameter of the fine granules is 300 to 400 μm.
 34. Fine granules ofclaim 32, wherein the particle diameter of the fine granules ispractically 425 μm or less.
 35. Fine granules of claim 32, wherein theparticle diameter of the fine granules is practically 400 μm or less.36. Fine granules of claim 32, wherein the acid-labile physiologicallyactive substance is a benzimidazole compound or a salt thereof.
 37. Finegranules of claim 36, wherein the benzimidazole compound islansoprazole.
 38. Fine granules of claim 32, wherein the basic inorganicsalt is a salt of magnesium and/or a salt of calcium.
 39. Fine granulesof claim 32, wherein the composition comprises a core being coated by abenzimidazole compound and a basic inorganic salt, said core comprisingcrystalline cellulose and lactose.
 40. Fine granules of claim 39,wherein the core comprises 50 weight % or more of lactose.
 41. Finegranules of claim 32, wherein the composition comprises 25 to 40 weight% of an acid-labile physiologically active substance.
 42. Fine granulesof claim 32, which are produced by fluidized-bed granulation method. 43.Fine granules of claim 32, wherein the enteric coating layer comprisesan aqueous enteric polymer agent.
 44. Fine granules of claim 43, whereinthe aqueous enteric polymer agent is a methacrylate copolymer.
 45. Finegranules of claim 43, wherein the enteric coating layer further comprisea sustained-release agent.
 46. Fine granules of claim 45, wherein thesustained-release agent is a methacrylate copolymer.
 47. Fine granulesof claim 45, wherein the sustained-release agent is in an amount of 5 to15 weight % relative to 100 weight % of the aqueous enteric polymeragent.
 48. Fine granules of claim 32, wherein the enteric coating layeris in an amount of 50 to 70 weight % relative to 100 weight % of thefine granules.
 49. A tablet, granule, fine granule, capsule,effervescent or suspension preparation which comprises the fine granulesof claim 32.